metricas
covid
Buscar en
Clinics
Toda la web
Inicio Clinics MicroRNA-15a/β1,4-GalT-I axis contributes to cartilage degeneration via NF-κB ...
Journal Information

Statistics

Follow this link to access the full text of the article

Original articles
MicroRNA-15a/β1,4-GalT-I axis contributes to cartilage degeneration via NF-κB signaling in osteoarthritis
Hairong Wang, Weilin Wang, Jian Wang, Linsheng Zhang, Yujie Luo, Xiaobo Tang
Corresponding author
19962412626@163.com

Corresponding author.
Department of Orthopedics, Jianhu People's Hospital, Yancheng, Jiangsu, China
Read
743
Times
was read the article
218
Total PDF
525
Total HTML
Share statistics
 array:23 [
  "pii" => "S180759322300090X"
  "issn" => "18075932"
  "doi" => "10.1016/j.clinsp.2023.100254"
  "estado" => "S300"
  "fechaPublicacion" => "2023-01-01"
  "aid" => "100254"
  "copyright" => "HCFMUSP"
  "copyrightAnyo" => "2023"
  "documento" => "article"
  "crossmark" => 1
  "subdocumento" => "fla"
  "cita" => "Clinics. 2023;78C:"
  "abierto" => array:3 [
    "ES" => false
    "ES2" => false
    "LATM" => false
  ]
  "gratuito" => false
  "lecturas" => array:1 [
    "total" => 0
  ]
  "itemSiguiente" => array:18 [
    "pii" => "S1807593223000789"
    "issn" => "18075932"
    "doi" => "10.1016/j.clinsp.2023.100242"
    "estado" => "S300"
    "fechaPublicacion" => "2023-01-01"
    "aid" => "100242"
    "copyright" => "HCFMUSP"
    "documento" => "article"
    "crossmark" => 1
    "subdocumento" => "fla"
    "cita" => "Clinics. 2023;78C:"
    "abierto" => array:3 [
      "ES" => false
      "ES2" => false
      "LATM" => false
    ]
    "gratuito" => false
    "lecturas" => array:1 [
      "total" => 0
    ]
    "en" => array:12 [
      "idiomaDefecto" => true
      "cabecera" => "<span class="elsevierStyleTextfn">Original articles</span>"
      "titulo" => "The nonsynaptic plasticity in Parkinson&#39;s disease&#58; Insights from an animal model"
      "tienePdf" => "en"
      "tieneTextoCompleto" => "en"
      "tieneResumen" => array:2 [
        0 => "en"
        1 => "en"
      ]
      "contieneResumen" => array:1 [
        "en" => true
      ]
      "contieneTextoCompleto" => array:1 [
        "en" => true
      ]
      "contienePdf" => array:1 [
        "en" => true
      ]
      "resumenGrafico" => array:2 [
        "original" => 0
        "multimedia" => array:8 [
          "identificador" => "fig0004"
          "etiqueta" => "Fig&#46; 4"
          "tipo" => "MULTIMEDIAFIGURA"
          "mostrarFloat" => true
          "mostrarDisplay" => false
          "figura" => array:1 [
            0 => array:4 [
              "imagen" => "gr4.jpeg"
              "Alto" => 2246
              "Ancho" => 3583
              "Tamanyo" => 1222367
            ]
          ]
          "detalles" => array:1 [
            0 => array:3 [
              "identificador" => "alt0004"
              "detalle" => "Fig "
              "rol" => "short"
            ]
          ]
          "descripcion" => array:1 [
            "en" => "<p id="spara004" class="elsevierStyleSimplePara elsevierViewall">Evaluation of astroglial reactivity in the striatal injured region investigated with immureactivity to GFAP in the groups submitted to the injection of 6-OHDA &#40;B&#41; and in the Control group &#40;A&#41;&#46; The GFAP staining is clear in &#40;B&#41;&#44; with the presence of reactive&#47;hypertrophic astrocytes with large cell bodies and thick cytoskeletal processes&#44; which can be seing in higher magnification &#40;E&#41;&#46; The monofactor analysis of variance of the optical densitometry data showed a significant increase in the intensity of GFAP staining in the lesional region&#44; confirming the observation verified in E&#44; in relation to the contralateral region &#40;F&#41; and the control group &#40;C and D&#41;&#46; The quantitave analysis shows that the glial reactivation process occurred specifically due to the 6-OHDA&#44; and not due to the lesion promoted by the injection&#44; as can be seen in Figures &#40;C&#41; and &#40;D&#41; and the statistical data&#46; GFAP immunoreactivity is also observed in reactive astrocytes in regions adjacent to the lesion observed by TH immunoreactivity &#40;<a class="elsevierStyleCrossRef" href="#fig0001">Fig&#46; 1</a>&#41;&#44; which demonstrates a spread of astrocytic reactivity processes&#46; &#42; Indicates <span class="elsevierStyleItalic">p</span> &#60; 0&#46;05&#46;</p>"
          ]
        ]
      ]
      "autores" => array:1 [
        0 => array:2 [
          "autoresLista" => "M&#244;nica P&#46;C&#46; Viegas, Luiz E&#46;C&#46; Santos, Mayra C&#46; Aar&#227;o, Samyra G&#46; Cecilio, Joana M&#46; Medrado, Arthur C&#46; Pires, Ant&#244;nio M&#46; Rodrigues, Carla A&#46; Scorza, Marcelo A&#46; Moret, Josef Finsterer, Fulvio A&#46; Scorza, Ant&#244;nio-Carlos G&#46; Almeida"
          "autores" => array:12 [
            0 => array:2 [
              "nombre" => "M&#244;nica P&#46;C&#46;"
              "apellidos" => "Viegas"
            ]
            1 => array:2 [
              "nombre" => "Luiz E&#46;C&#46;"
              "apellidos" => "Santos"
            ]
            2 => array:2 [
              "nombre" => "Mayra C&#46;"
              "apellidos" => "Aar&#227;o"
            ]
            3 => array:2 [
              "nombre" => "Samyra G&#46;"
              "apellidos" => "Cecilio"
            ]
            4 => array:2 [
              "nombre" => "Joana M&#46;"
              "apellidos" => "Medrado"
            ]
            5 => array:2 [
              "nombre" => "Arthur C&#46;"
              "apellidos" => "Pires"
            ]
            6 => array:2 [
              "nombre" => "Ant&#244;nio M&#46;"
              "apellidos" => "Rodrigues"
            ]
            7 => array:2 [
              "nombre" => "Carla A&#46;"
              "apellidos" => "Scorza"
            ]
            8 => array:2 [
              "nombre" => "Marcelo A&#46;"
              "apellidos" => "Moret"
            ]
            9 => array:2 [
              "nombre" => "Josef"
              "apellidos" => "Finsterer"
            ]
            10 => array:2 [
              "nombre" => "Fulvio A&#46;"
              "apellidos" => "Scorza"
            ]
            11 => array:2 [
              "nombre" => "Ant&#244;nio-Carlos G&#46;"
              "apellidos" => "Almeida"
            ]
          ]
        ]
      ]
      "resumen" => array:1 [
        0 => array:3 [
          "titulo" => "Highlights"
          "clase" => "author-highlights"
          "resumen" => "<span id="abss0001" class="elsevierStyleSection elsevierViewall"><p id="spara006" class="elsevierStyleSimplePara elsevierViewall"><ul class="elsevierStyleList" id="celist0001"><li class="elsevierStyleListItem" id="celistitem0001"><span class="elsevierStyleLabel">&#8226;</span><p id="para0001" class="elsevierStylePara elsevierViewall">6-OHDA lesioned striatum without changes in CCC cotransporters and Na&#43;&#47;<span class="elsevierStyleItalic">K</span>&#43;-atpase&#46;</p></li><li class="elsevierStyleListItem" id="celistitem0002"><span class="elsevierStyleLabel">&#8226;</span><p id="para0002" class="elsevierStylePara elsevierViewall">However&#44; was observed astrocytic reactivity&#46;</p></li><li class="elsevierStyleListItem" id="celistitem0003"><span class="elsevierStyleLabel">&#8226;</span><p id="para0003" class="elsevierStylePara elsevierViewall">Dopaminergic degeneration was followed by changes in connexin-36&#46;</p></li></ul></p></span>"
        ]
      ]
    ]
    "idiomaDefecto" => "en"
    "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1807593223000789?idApp=UINPBA00004N"
    "url" => "/18075932/000000780000000C/v4_202409020811/S1807593223000789/v4_202409020811/en/main.assets"
  ]
  "itemAnterior" => array:18 [
    "pii" => "S1807593223000893"
    "issn" => "18075932"
    "doi" => "10.1016/j.clinsp.2023.100253"
    "estado" => "S300"
    "fechaPublicacion" => "2023-01-01"
    "aid" => "100253"
    "copyright" => "HCFMUSP"
    "documento" => "article"
    "crossmark" => 1
    "subdocumento" => "fla"
    "cita" => "Clinics. 2023;78C:"
    "abierto" => array:3 [
      "ES" => false
      "ES2" => false
      "LATM" => false
    ]
    "gratuito" => false
    "lecturas" => array:1 [
      "total" => 0
    ]
    "en" => array:12 [
      "idiomaDefecto" => true
      "cabecera" => "<span class="elsevierStyleTextfn">Original articles</span>"
      "titulo" => "METTL3 promotes hyperoxia-induced pyroptosis in neonatal bronchopulmonary dysplasia by inhibiting ATG8-mediated autophagy"
      "tienePdf" => "en"
      "tieneTextoCompleto" => "en"
      "tieneResumen" => array:2 [
        0 => "en"
        1 => "en"
      ]
      "contieneResumen" => array:1 [
        "en" => true
      ]
      "contieneTextoCompleto" => array:1 [
        "en" => true
      ]
      "contienePdf" => array:1 [
        "en" => true
      ]
      "resumenGrafico" => array:2 [
        "original" => 0
        "multimedia" => array:8 [
          "identificador" => "fig0004"
          "etiqueta" => "Fig&#46; 4"
          "tipo" => "MULTIMEDIAFIGURA"
          "mostrarFloat" => true
          "mostrarDisplay" => false
          "figura" => array:1 [
            0 => array:4 [
              "imagen" => "gr4.jpeg"
              "Alto" => 1991
              "Ancho" => 3583
              "Tamanyo" => 574631
            ]
          ]
          "detalles" => array:1 [
            0 => array:3 [
              "identificador" => "alt0004"
              "detalle" => "Fig "
              "rol" => "short"
            ]
          ]
          "descripcion" => array:1 [
            "en" => "<p id="spara004" class="elsevierStyleSimplePara elsevierViewall">METTL3 mediates the m6A modification of ATG8&#46; &#40;A&#8210;C&#41; ATG8 protein expression detected by western blot&#46; &#40;D&#41; The potential m6A modification sites were predicted by SCRAMP&#46; &#40;E&#8210;G&#41; The potential m6A modification sites verified by MeRIP assay&#46; &#42;&#42;p &#60; 0&#46;01&#46; Data represent at least three independent sets of experiments&#46;</p>"
          ]
        ]
      ]
      "autores" => array:1 [
        0 => array:2 [
          "autoresLista" => "Lili Xu, Zhan Shi, Zhaojun Pan, Rong Wu"
          "autores" => array:4 [
            0 => array:2 [
              "nombre" => "Lili"
              "apellidos" => "Xu"
            ]
            1 => array:2 [
              "nombre" => "Zhan"
              "apellidos" => "Shi"
            ]
            2 => array:2 [
              "nombre" => "Zhaojun"
              "apellidos" => "Pan"
            ]
            3 => array:2 [
              "nombre" => "Rong"
              "apellidos" => "Wu"
            ]
          ]
        ]
      ]
      "resumen" => array:1 [
        0 => array:3 [
          "titulo" => "Highlights"
          "clase" => "author-highlights"
          "resumen" => "<span id="abss0001" class="elsevierStyleSection elsevierViewall"><p id="spara008" class="elsevierStyleSimplePara elsevierViewall"><ul class="elsevierStyleList" id="celist0001"><li class="elsevierStyleListItem" id="celistitem0001"><span class="elsevierStyleLabel">&#8226;</span><p id="para0002" class="elsevierStylePara elsevierViewall">m6A modification participates in the development of BPD&#46;</p></li><li class="elsevierStyleListItem" id="celistitem0002"><span class="elsevierStyleLabel">&#8226;</span><p id="para0003" class="elsevierStylePara elsevierViewall">METTL3 promotes the pyroptosis of BEAS-2B cells&#46;</p></li><li class="elsevierStyleListItem" id="celistitem0003"><span class="elsevierStyleLabel">&#8226;</span><p id="para0004" class="elsevierStylePara elsevierViewall">ETTL3-mediated m6A modification of ATG8 disrupts the interaction between ATG8 and GSDMD&#46;</p></li></ul></p></span>"
        ]
      ]
    ]
    "idiomaDefecto" => "en"
    "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1807593223000893?idApp=UINPBA00004N"
    "url" => "/18075932/000000780000000C/v4_202409020811/S1807593223000893/v4_202409020811/en/main.assets"
  ]
  "en" => array:20 [
    "idiomaDefecto" => true
    "cabecera" => "<span class="elsevierStyleTextfn">Original articles</span>"
    "titulo" => "MicroRNA-15a&#47;&#946;1&#44;4-GalT-I axis contributes to cartilage degeneration via NF-&#954;B signaling in osteoarthritis"
    "tieneTextoCompleto" => true
    "autores" => array:1 [
      0 => array:4 [
        "autoresLista" => "Hairong Wang, Weilin Wang, Jian Wang, Linsheng Zhang, Yujie Luo, Xiaobo Tang"
        "autores" => array:6 [
          0 => array:2 [
            "nombre" => "Hairong"
            "apellidos" => "Wang"
          ]
          1 => array:2 [
            "nombre" => "Weilin"
            "apellidos" => "Wang"
          ]
          2 => array:2 [
            "nombre" => "Jian"
            "apellidos" => "Wang"
          ]
          3 => array:2 [
            "nombre" => "Linsheng"
            "apellidos" => "Zhang"
          ]
          4 => array:2 [
            "nombre" => "Yujie"
            "apellidos" => "Luo"
          ]
          5 => array:4 [
            "nombre" => "Xiaobo"
            "apellidos" => "Tang"
            "email" => array:1 [
              0 => "19962412626@163.com"
            ]
            "referencia" => array:1 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">&#42;</span>"
                "identificador" => "cor0001"
              ]
            ]
          ]
        ]
        "afiliaciones" => array:1 [
          0 => array:2 [
            "entidad" => "Department of Orthopedics&#44; Jianhu People&#39;s Hospital&#44; Yancheng&#44; Jiangsu&#44; China"
            "identificador" => "aff0001"
          ]
        ]
        "correspondencia" => array:1 [
          0 => array:3 [
            "identificador" => "cor0001"
            "etiqueta" => "&#8270;"
            "correspondencia" => "Corresponding author&#46;"
          ]
        ]
      ]
    ]
    "resumenGrafico" => array:2 [
      "original" => 0
      "multimedia" => array:8 [
        "identificador" => "fig0001"
        "etiqueta" => "Fig&#46; 1"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr1.jpeg"
            "Alto" => 1630
            "Ancho" => 2833
            "Tamanyo" => 522235
          ]
        ]
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "alt0001"
            "detalle" => "Fig "
            "rol" => "short"
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spara001" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Expression of &#946;1&#44;4-GalT-I is elevated in the articular cartilage of DMM-induced OA mice</span>&#46; The mice were randomly assigned to a DMM group and a Sham group&#44; with six mice in each group&#46; &#40;A and B&#41; Representative images of articular cartilage stained with H&#38;E &#40;A&#41; and safranin O-fast green &#40;B&#41; &#40;scale bar&#58; 100 &#956;m&#41;&#46; &#40;C&#41; OARSI score of the joints&#46; &#40;D and E&#41; The qPCR and western blot were used to detect mRNA and protein expression of &#946;1&#44;4-GalT-I in articular cartilage &#40;&#42;&#42;&#42; p &#60; 0&#46;001&#44; &#42;&#42; p &#60; 0&#46;01&#41;&#46;</p>"
        ]
      ]
    ]
    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0001" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0008">Introduction</span><p id="para0009" class="elsevierStylePara elsevierViewall">Aging and long-term mechanical stress&#44; both of which cause articular cartilage deterioration&#44; are the leading causes of Osteoarthritis &#40;OA&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0001"><span class="elsevierStyleSup">1</span></a> Chondrocytes are the most widely known type of cell found in the cartilage matrix&#44; which is responsible for maintaining the matrix&#39;s homeostasis <a class="elsevierStyleCrossRef" href="#bib0002"><span class="elsevierStyleSup">2</span></a>&#46; A growing body of studies have reported that some genes were dysregulated in chondrocytes&#44; which caused abnormal proliferation and inflammation responses&#44; thereby facilitating cartilage degeneration&#46;<a class="elsevierStyleCrossRef" href="#bib0003"><span class="elsevierStyleSup">3</span></a><a class="elsevierStyleCrossRef" href="#bib0004"><span class="elsevierStyleSup">4</span></a></p><p id="para0010" class="elsevierStylePara elsevierViewall">&#946;1&#44; 4-Galactosyltransferase-I &#40;&#946;1&#44;4-GalT-I&#41; is an essential enzyme in a variety of biological activities&#44; including glucose metabolism&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">5</span></a> Immune cell adhesion at the site of inflammation was related to increased &#946;1&#44;4-GalT-I in articular cartilage as well as synovial tissue of OA patients as compared to the sane&#46;<a class="elsevierStyleCrossRef" href="#bib0006"><span class="elsevierStyleSup">6</span></a> By decreasing Toll-Like Receptor 4 &#40;TLR4&#41; signaling and p65 and IKK phosphorylation&#44; &#946;1&#44;4-GalT-I has also been demonstrated to diminish joint inflammation and prevent chondrocyte apoptosis in OA&#46;<a class="elsevierStyleCrossRef" href="#bib0007"><span class="elsevierStyleSup">7</span></a> According to previous research&#44;<a class="elsevierStyleCrossRef" href="#bib0008"><span class="elsevierStyleSup">8</span></a> &#946;1&#44;4-GalT-I is significantly elevated in the synovial tissue of rheumatoid arthritis patients&#44; which is involved in the inflammatory response of synovial tissue&#46; Furthermore&#44; in a surgically induced OA model&#44; the expression of &#946;1&#44;4-GalT-I was found to be increased on the first day after the operation&#46;<a class="elsevierStyleCrossRef" href="#bib0009"><span class="elsevierStyleSup">9</span></a> These findings suggest that &#946;1&#44;4-GalT-I plays a crucial role in the development and progression of inflammation in the synovial tissue associated with OA&#46;</p><p id="para0011" class="elsevierStylePara elsevierViewall">MicroRNAs &#40;miRNAs&#41; are one type of epigenetic modulator that can regulate the protein levels of the targeted mRNAs&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">10</span></a> Recent studies have progressively confirmed miRNAs can be combined with the 3&#8217;-Untranslated Region &#40;UTR&#41; of targeted mRNA to result in the irreversible degradation of mRNA&#44; thereby regulating the development and progression of diverse diseases&#44; including OA&#46;<a class="elsevierStyleCrossRef" href="#bib0011"><span class="elsevierStyleSup">11</span></a> Over the past decade&#44; multiple miRNAs have been implicated in OA progression by the involvement of the degradation of Extracellular Matrix &#40;ECM&#41; and cartilage degeneration&#46;<a class="elsevierStyleCrossRef" href="#bib0012"><span class="elsevierStyleSup">12</span></a></p><p id="para0012" class="elsevierStylePara elsevierViewall">For example&#44; by inhibiting the nuclear factor-erythroid 2-related factor 2 as well as the antioxidant capacity of chondrocytes&#44; miR-146a promotes cartilage degeneration&#46;<a class="elsevierStyleCrossRef" href="#bib0013"><span class="elsevierStyleSup">13</span></a> Through suppression of the Nuclear Factor-kappaB &#40;NF-&#954;&#914;&#41; signaling&#44; inhibition of miR-140 and miR-146a reduced the inflammatory response to OA&#46;<a class="elsevierStyleCrossRef" href="#bib0014"><span class="elsevierStyleSup">14</span></a> Moreover&#44; miR-26a reduced articular cartilage damage and synovial inflammation in OA by inhibiting the NF-&#922;&#946;&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">15</span></a> However&#44; the exact miRNAs that directly regulate &#946;1&#44;4-GalT-I during OA development remain elusive&#46;</p><p id="para0013" class="elsevierStylePara elsevierViewall">In the present study&#44; the authors found that miR-15a was a direct regulator of &#946;1&#44; 4-GalT-I in osteoarthritic chondrocytes and uncovered the role of miR-15a&#47;&#946;1&#44; 4-GalT-I axis in cartilage degeneration based on <span class="elsevierStyleItalic">in vitro</span> and <span class="elsevierStyleItalic">in vivo</span> analysis&#46; The present results clarify that the miR-15a&#47;&#946;1&#44; 4-GalT-I axis inhibits NF-&#954;B phosphorylation to reduce ECM degradation and senescence in chondrocytes&#44; thereby ameliorating cartilage degeneration in OA&#46; Future treatments for OA could focus on miR-15a and &#946;1&#44; 4-GalT-I as possible therapeutic targets&#46;</p></span><span id="sec0002" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0009">Materials &#38; methods</span><span id="sec0003" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0010">Animal model establishment and intervention</span><p id="para0014" class="elsevierStylePara elsevierViewall">A total of 36 male C57BL&#47;6 mice that were specifically pathogen-free and weighed 28&#177;2g and 10 weeks old were acquired from the Animal Experiment Center of Jiangsu University&#46; At the animal experiment center&#44; all of the mice were housed in an area free of specific pathogens and given unfettered access to food and water&#46; The temperature was kept at 25&#160;&#176;C&#44; and the relative humidity ranged from 50 to 60 percent&#46; Microsurgical techniques were utilized in order to develop a mouse model of OA that included a Destabilization of the Medial Meniscus &#40;DMM&#41;&#44; with reference to previously published material&#46;<a class="elsevierStyleCrossRef" href="#bib0016"><span class="elsevierStyleSup">16</span></a> Twelve mice&#44; six in each of the Sham and DMM groups&#44; were euthanized six weeks after surgery to acquire joint and tissue samples&#46; There were six mice in each of the following groups&#58; Sham&#44; DMM&#44; DMM&#160;&#43;&#160;Lentivirus &#40;Lv&#41;-NC&#44; and DMM&#160;&#43;&#160;Lv-miR-15a&#46; Then&#44; a week after surgery&#44; each group underwent weekly intra-articular injections of 0&#46;9&#37; NaCl &#40;10&#160;&#956;L&#41;&#44; 0&#46;9&#37; NaCl &#40;10&#160;&#956;L&#41;&#44; Lv-NC &#40;20 mmoL&#47;L&#44; 10 &#956;L&#41;&#44; and Lv-miR-15a &#40;20&#160;mmoL&#47;L&#44; 10&#160;&#956;L&#41;&#44; respectively&#46; The experiments involving animals in this study strictly followed the ARRIVE guidelines&#46;<a class="elsevierStyleCrossRef" href="#bib0017"><span class="elsevierStyleSup">17</span></a> Every procedure was approved by the Animal Care and Use Committee of Jianhu People&#39;s Hospital &#40;protocol n&#176; 2021JH009&#41;&#46;</p></span><span id="sec0004" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0011">Cell culture and treatment <span class="elsevierStyleItalic">in vitro</span></span><p id="para0015" class="elsevierStylePara elsevierViewall">Merck Millipore &#40;California&#44; USA&#41; supplied the human normal chondrocyte cell line &#40;C28&#47;I2&#41;&#46; At a situation of 37&#160;&#176;C as well as 5&#37; carbon dioxide&#44; cells were cultured in Dulbecco&#39;s modified Eagle&#39;s medium&#47;F-12 &#40;Gibco&#44; USA&#41; supplemented with 10&#37; fetal bovine serum &#40;Gibco&#44; USA&#41; and added with 1&#37; streptomycin and penicillin &#40;Gibco&#44; USA&#41;&#46; IL-1&#946; &#40;Proteintech&#44; USA&#41; at 10&#160;ng&#47;mL was employed to stimulate chondrocytes in order to produce a mimetic OA model <span class="elsevierStyleItalic">in vitro</span>&#46; Chondrocytes cultivated in vitro were separated into five groups&#58; IL-1&#946;&#44; miR-15a mimic&#160;&#43;&#160;IL-1&#946;&#44; &#946;1&#44;4-GalT-1 OE&#160;&#43;&#160;IL-1&#946;&#44; IL-1&#946;&#160;&#43;&#160;miR-15a mimic&#160;&#43;&#160;&#946;1&#44;4-GalT-1 OE and control group&#46; Following transfection&#44; chondrocytes in the group that contained IL-1&#946; were subjected to stimulation with IL-1&#946; &#40;10&#160;ng&#47;mL&#41; for 24&#160;h&#44; whereas the control group was grown under conditions without IL-1&#946; for one day&#46; Then&#44; each group&#39;s cells were utilized for subsequent tests&#46;</p></span><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0012">Transfection</span><p id="para0016" class="elsevierStylePara elsevierViewall">The miR-15a mimics&#44; the &#946;1&#44;4-GalT-I overexpression vector&#44; the Negative Control &#40;NC&#41;-Lentivirus &#40;Lv-NC&#41;&#44; and the overexpression miR-15a-Lentivirus &#40;Lv-miR-15a&#41; used in the present study were afforded by the RiboBio biotechnology company &#40;Guangdong province&#44; Guangzhou&#44; China&#41;&#46; In accordance with what is outlined in the manual provided by the manufacturer&#44; chondrocytes were effectively transfected with miR-15a mimics and 1&#44;4-GalT-I overexpression vectors at an ultimate dose at 50 nM&#44; employing Lipofectamine 3000 reagent &#40;Thermo Fisher Scientific&#44; USA&#41;&#46;</p></span><span id="sec0006" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0013">Histopathological analysis</span><p id="para0017" class="elsevierStylePara elsevierViewall">After soaking for 24&#160;h in 4&#37; paraformaldehyde&#44; knee tissue from a mouse was decalcified by soaking it for 20 days in a 10&#37; Ethylene Diamine Tetraacetic Acid &#40;EDTA&#41; solution&#46; After decalcification was complete&#44; the samples were cleaned with distilled water before being examined&#44; and then immersed for 8 hours in 70&#44; 80&#44; 90&#44; 95 and 100&#37; ethanol to dehydrate&#46; Paraffin embedding was then performed&#46; The samples were cut to 4&#160;&#956;m thickness&#46; Following the articulated directions in the instructions offered by the manufacturer&#44; the sections were dewaxed as well as hydrated prior to being stained with safranin O-fast green staining and Haematoxylin and Eosin &#40;H&#38;E&#41; staining&#46; For the purpose of determining the level of damage to cartilage tissue&#44; the Osteoarthritis Research Society International &#40;OARSI&#41; scoring criteria were applied&#46;</p></span><span id="sec0007" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0014">Quantitative real-time polymerase chain reaction &#40;qPCR&#41;</span><p id="para0018" class="elsevierStylePara elsevierViewall">The Trizol reagent &#40;Thermo Fisher Scientific&#44; USA&#41; was used to successfully extract RNA after a cartilage tissue was ground with liquid nitrogen&#46; Utilizing the FastKing cDNA 1<span class="elsevierStyleSup">st</span> Strand Synthesis Kit &#40;Tengen&#44; KR116-01&#41;&#44; RNA was converted into cDNA from 1g of total RNA in a reverse transcription reaction&#46; PCR was carried out using cDNA serving as the template&#44; and the process was conducted in accordance with the guidelines offered in the TaKaRa SYBR Premix Ex Taq II kit&#46; The amplification conditions were 95&#160;&#176;C for 4&#160;min&#44; 94&#160;&#176;C for 30&#160;s&#44; 62&#160;&#176;C for 40&#160;s&#44; 72&#160;&#176;C for 45&#160;s&#44; and the above for 35 cycles&#44; and finally at 72&#160;&#176;C for 10 minutes&#46; During the final cycle&#44; amplification curves&#44; lysis curves&#44; and CT values were collected&#46; This study used GAPDH as an internal reference gene&#46; The calculation of the gene expression was carried out using the 2<span class="elsevierStyleSup">&#8722;&#916;&#916;Ct</span> method&#46;<a class="elsevierStyleCrossRef" href="#bib0018"><span class="elsevierStyleSup">18</span></a> Supplementary Table S1 displays the primer sequences used in this experiment&#46;</p></span><span id="sec0008" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0015">Western blot</span><p id="para0019" class="elsevierStylePara elsevierViewall">The grinding technique with liquid nitrogen was used to accomplish the procedure of tissue lysis on the knee cartilage&#46; Chondrocytes were lysed using RIPA lysis solution&#46; The total concentration of protein in each sample was calculated using a BCA kit&#46; Then protein samples were denatured in water at 100&#160;&#176;C for 5&#160;min&#46; After the proteins had been denatured&#44; 30&#160;&#181;g each protein sample was processed through an SDS-PAGE gel electrophoresis&#46; Subsequently&#44; proteins in SDS-PAGE gel are transferred to the PVDF membrane by electrophoresis&#46; Electrophoresis conditions were set at 80V for 20 minutes&#44; followed by 1 hour at 120V&#46; Protein transfer to PVDF membranes was done at 120V for 1&#46;5&#160;h&#46; PVDF membranes were sealed with skimmed milk at a solution of 5&#37; for one hour at ambient temperature&#46; After completion of membrane washing with TBST solution&#44; the membranes were incubated with primary antibodies at 4&#160;&#176;C overnight&#46; The membrane was then washed with TBST solution&#46; Upon completion of the washing of the membranes with the TBST solution&#44; membranes were incubated with the primary antibodies for a period of one night at 4&#160;&#176;C&#46; After that&#44; in order to eliminate proteins that did not stick to the membrane&#44; it was washed on the shaker with TBST solution&#46; The membranes were incubated with corresponding Horseradish Peroxidase &#40;HRP&#41; &#8210; conjugated secondary antibodies for 2&#160;h at ambient temperature&#46; Upon washing the membrane with the TBST&#44; it was color developed by an ECL reagent&#46; Subsequently&#44; a ChemiDoc Touch &#40;Bio-Rad&#44; USA&#41; was used to capture the images&#46; Bands were analyzed for grey scale values using Image J software&#46; &#946;-actin was used as the inner control of the protein expression&#46; Supplementary Table 2 contains information about the antibodies&#46;</p></span><span id="sec0009" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0016">Prediction of target sites by TargetScan</span><p id="para0020" class="elsevierStylePara elsevierViewall">Referring to previously published literature&#44;<a class="elsevierStyleCrossRef" href="#bib0019"><span class="elsevierStyleSup">19</span></a> the authors were able to estimate the targeted site of miR-15a at 1&#44;4-GalT-I by using the TargetScan website&#44; which can be accessed online at <a href="https://www.targetscan.org">https&#58;&#47;&#47;www&#46;targetscan&#46;org</a>&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0017">Dual-luciferase constructs and reporter assay</span><p id="para0021" class="elsevierStylePara elsevierViewall">The binding of &#946;1&#44;4-GalT-I gene to the miR-15a was <span class="elsevierStyleItalic">in vitro</span> elucidated by a luciferase reporter assay&#46; The 3&#8242;-UTR sequence in &#946;1&#44;4-GalT-I was obtained using the NCBI database&#46; The corresponding primer sequences were synthesized&#44; and the recombinant plasmids were constructed by Guangzhou Ribo Bioengineering Company&#46; The 3&#8242;-UTR sequence in &#946;1&#44;4-GalT-I gene was successfully amplified by PCR and ligated using GV272 as a vector to construct the wild-type GV272-&#946;1&#44;4-GalT-I-WT 3&#8242;-UTR and mutant GV272-&#946;1&#44;4-GalT-I-MUT 3&#8242;-UTR of the recombinant plasmids&#46; Then&#44; Negative Control &#40;NC&#41; and miR-15a mimics were synchronously transfected with these two recombinant plasmids into HEK293T cells&#44; respectively&#44; according to the directions for the X-tremeGENE HP DNA Transfection Reagent &#40;CAS&#58; 06366244001&#44; Roche&#44; Switzerland&#41;&#46; In order to determine the level of luciferase activity present in the samples&#44; the Luciferase Assay Reagent II and the Stop &#38; Glo&#174; reagent were added to them in accordance with the protocols outlined in the Dual-Luciferase&#174; Reporter Assay System &#40;Promega&#44; USA&#44; CAS&#58; e1910&#41;&#46; The absorbance was measured on a Multiskan FC ELISA &#40;Thermo&#44; USA&#41;&#46;</p><p id="para0022" class="elsevierStylePara elsevierViewall">The pGL3-NF-&#954;B-Pro reporter gene recombinant plasmid was purchased from Guangzhou Ribo Bioengineering Company&#46; Transfection of plasmids into chondrocytes was conducted&#44; using the X-tremeGENE HP DNA Transfection Reagent &#40;CAS&#58; 06366244001&#44; Roche&#44; Switzerland&#41;&#46; The luciferase activity was then tested as described above&#46;</p></span><span id="sec0011" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0018">Enzyme-linked immunosorbent assays &#40;ELISA&#41;</span><p id="para0023" class="elsevierStylePara elsevierViewall">The supernatant was collected following the <span class="elsevierStyleItalic">in vitro</span> cultivation of chondrocytes&#44; and then it was centrifuged at a temperature of 4&#176;C for 5 minutes at a speed of 1500 rpm&#46; The collected supernatant after centrifugation was used for protein concentration assays&#46; The High Mobility Group Protein B1 &#40;HMGB-1&#41; ELISA Kit &#40;FineTest&#44; cat&#46;no EM0382&#41;&#44; as well as the TNF-&#945; ELISA Kit &#40;FineTest&#44; cat&#46;no EM0183&#41;&#44; were utilized in order to assess the concentrations of soluble HMGB-1 and TNF-&#945;&#44; respectively&#44; in line with the directions that have been supplied by the respective manufacturers&#46; Finally&#44; the absorbance at 450&#160;nm was measured using a Microplate Reader &#40;Reagen&#44; Beijing&#44; China&#41;&#46;</p></span><span id="sec0012" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0019">Assay of senescence-associated &#946;-galactosidase &#40;SA-&#946;-Gal&#41; activity</span><p id="para0024" class="elsevierStylePara elsevierViewall">The senescence-associated -galactosidase staining Kit was utilized in order to determine the level of &#946;-galactosidase activity present in vitro cultured chondrocytes&#46; Chondrocytes were cultured in a 6-well cell culture plate &#40;Beygold&#44; China&#41;&#46; Cells were gently rinsed once using PBS&#46; After adding 500&#160;&#956;L of a 4&#37; paraformaldehyde solution&#44; the mixture was left to fix at ambient temperature for 5&#160;min&#46; Subsequently&#44; the paraformaldehyde was removed&#46; The cells were then washed two times by PBS&#46; Each well added one milliliter of SA-gal staining solution and was incubated for 12&#160;h at 37&#160;&#176;C&#46; The number of cells that showed a positive reaction to the SA-&#946;-gal stain was counted under an inverted microscope&#46;</p></span><span id="sec0013" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0020">Immunofluorescence</span><p id="para0025" class="elsevierStylePara elsevierViewall">Chondrocytes were stained immunofluorescently to observe NF-B localization&#46; Coverslips made of sterile material were placed in each well of culture plates with 24 wells&#46; Then&#44; chondrocytes in the logarithmic growth phase &#40;the control group&#44; IL-1&#946; group&#44; miR-15a mimic&#160;&#43;&#160;IL-1&#946; group&#44; &#946;1&#44;4-GalT-1 OE&#160;&#43;&#160;IL-1&#946; group&#44; IL-1&#946;&#160;&#43;&#160;miR-15a mimic&#160;&#43;&#160;&#946;1&#44;4-GalT-1 OE group&#41; were inoculated at 5&#215;10<span class="elsevierStyleSup">4</span> cells&#47;well in the treated plates and continued to be cultured for 24&#160;h&#46; The cells were prepared by fixing them with 4&#37; paraformaldehyde &#40;Solarbio&#44; China&#41; and then permeabilizing them with 0&#46;3&#37; Triton X-100 reagent &#40;Solarbio&#44; China&#41;&#44; respectively&#46; Cells were incubated with 5&#37; BSA for 1 hour&#46; After adding the rabbit anti-human NF-kB p65 polyclonal antibody &#40;Abcam&#44; CAS&#58; ab16502&#41;&#44; the mixture was kept in a refrigerator at 4&#176;C for 8 hours&#46; Subsequently&#44; goat anti-rabbit IgG H&#38;L &#40;Alexa Fluor&#174; 488&#44; Abcam&#44; ab150077&#41; and DAPI were incubated for 2 hours and 10 minutes at ambient temperature&#44; protected from light&#44; respectively&#46; Fluorescence was observed&#44; and pictures were taken under an Eclipse E100&#43; inverted fluorescence microscope &#40;Nikon&#44; Japan&#41;&#46;</p></span><span id="sec0014" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0021">Statistical analysis</span><p id="para0026" class="elsevierStylePara elsevierViewall">GraphPad Prism 8&#46;0 was applied throughout the process of statistical analysis&#46;</p><p id="para0027" class="elsevierStylePara elsevierViewall">The results of the experimental data are expressed as the means &#177; standard deviations&#46; Calculating the statistical significance of the differences between the two groups involved the use of the unpaired two-tailed Student&#39;s <span class="elsevierStyleItalic">t</span>-test&#46; The One-Way ANOVA approach was utilized to make comparisons between a variety of different groups&#46; If the p-value was lower than 0&#46;05&#44; then the differences were determined to be statistically significant&#46; Correlations between miR-146a&#44; miR-140&#44; miR-26a&#44; miR-15a&#44; miR-9&#44; as well as &#946;1&#44;4-GalT-I were done by Pearson correlation analysis&#46;</p></span></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0022">Results</span><span id="sec0016" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0023">Expression of &#946;1&#44;4-GalT-I is elevated in the articular cartilage of DMM-induced OA mice</span><p id="para0028" class="elsevierStylePara elsevierViewall">In this study&#44; the authors successfully established the DMM mouse model of OA using microsurgical techniques&#46; When compared to the Sham group&#44; the results of H&#38;E staining and safranin O-fast green staining demonstrated that the DMM group had significantly reduced cartilage present in the knee and exhibited considerable damage of articular cartilage &#40;<a class="elsevierStyleCrossRef" href="#fig0001">Fig&#46; 1</a>A and&#46;<a class="elsevierStyleCrossRef" href="#fig0001">B</a>&#41;&#46; The OARSI scores of the DMM group were significantly higher than those of the Sham group &#40;<a class="elsevierStyleCrossRef" href="#fig0001">Fig&#46; 1</a>C&#44; p &#60; 0&#46;001&#41;&#46; When compared to the Sham group&#44; the mRNA and protein expression of &#946;1&#44;4-GalT-I in the articular cartilage of the DMM group were considerably higher than those found in the Sham group &#40;<a class="elsevierStyleCrossRef" href="#fig0001">Fig&#46; 1</a>D and E&#44; p &#60; 0&#46;01&#41;&#46;</p><elsevierMultimedia ident="fig0001"></elsevierMultimedia></span><span id="sec0017" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0024">MicroRNA-15a is down-regulated and negatively correlated with &#946;1&#44;4-GalT-I in articular cartilage of DMM-induced OA mice</span><p id="para0029" class="elsevierStylePara elsevierViewall">Through a literature review&#44; the authors collected several miRNAs associated with OA progression&#44; including miR-146a&#44; miR-15a&#44; miR-140&#44; miR-26a&#44; and miR-9&#46; The authors found that miR-146a&#44; miR-15a&#44; miR-140&#44; and miR-26a were reduced in expression in articular cartilage of DMM-induced OA mice&#44; compared with the sham group &#40;<a class="elsevierStyleCrossRef" href="#fig0002">Fig&#46; 2</a>A&#8210;E&#44; p &#60; 0&#46;05&#44; p &#60; 0&#46;01&#44; p &#60; 0&#46;01&#44; p &#60; 0&#46;01&#44; no significant difference&#44; respectively&#41;&#46; Pearson correlation coefficient analysis showed that miR-15a and miR-26a were negatively correlated with &#946;1&#44;4-GalT-I &#40;<a class="elsevierStyleCrossRef" href="#fig0002">Fig&#46; 2</a>G&#44; <a class="elsevierStyleCrossRef" href="#fig0002">p</a>&#160;&#61;&#160;0&#46;0113&#44; <span class="elsevierStyleItalic">r</span>&#160;&#61;&#160;-0&#46;6997&#59; <a class="elsevierStyleCrossRef" href="#fig0002">Fig&#46; 2I</a>&#44; <a class="elsevierStyleCrossRef" href="#fig0002">p</a>&#160;&#61;&#160;0&#46;0137&#44; <span class="elsevierStyleItalic">r</span>&#160;&#61;&#160;-0&#46;6866&#41;&#46; Considering that the correlation between &#946;1&#44;4-GalT-I and miR-15a was greater than that between &#946;1&#44;4-GalT-I and miR-26a&#44; the authors next performed an in-depth study of miR-15a&#46; The authors made chondrocytes stably overexpress miR-15a by transfection &#40;<a class="elsevierStyleCrossRef" href="#fig0002">Fig&#46; 2K</a>&#41;&#46; The binding site of miR-15a to the 3&#8242;UTR region of &#946;1&#44;4-GalT-I was predicted by TargetScan &#40;<a class="elsevierStyleCrossRef" href="#fig0002">Fig&#46; 2L</a>&#41;&#46; The binding of miR-15a with &#946;1&#44;4-GalT-I was verified by luciferase reporter analysis &#40;<a class="elsevierStyleCrossRef" href="#fig0002">Fig&#46; 2M</a>&#41;&#46; Moreover&#44; both mRNA and protein expression of &#946;1&#44;4-GalT-I were significantly reduced upon the overexpression of miR-15a &#40;<a class="elsevierStyleCrossRef" href="#fig0002">Fig&#46; 2</a><a class="elsevierStyleCrossRef" href="#fig0002">N</a>&#8210;O&#44; p &#60; 0&#46;01&#41;&#46; The above findings show that miR-15a can target and inhibit the transcription of &#946;1&#44;4-GalT-I&#46;</p><elsevierMultimedia ident="fig0002"></elsevierMultimedia></span><span id="sec0018" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0025">MiR-15a alleviated ECM degradation and cellular senescence in IL-1&#946;-induced chondrocytes by suppressing &#946;1&#44;4-GalT-I</span><p id="para0030" class="elsevierStylePara elsevierViewall">In order to simulate the chondrocytes found in OA&#44; the authors stimulated <span class="elsevierStyleItalic">in vitro</span> chondrocytes with IL-1&#946;&#46; The results showed that miR-15a expression appeared to decrease gradually with prolonged IL-1&#946; stimulation&#44; while protein expression of &#946;1&#44;4-GalT-I increased gradually &#40;<a class="elsevierStyleCrossRef" href="#fig0003">Fig&#46; 3</a> A and <a class="elsevierStyleCrossRef" href="#fig0003">B</a>&#41;&#46; Previous studies have identified extracellular matrix degradation and chondrocyte senescence as important mechanisms contributing to cartilage degeneration&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">20</span></a><a class="elsevierStyleCrossRef" href="#bib0021"><span class="elsevierStyleSup">21</span></a> In addition&#44; overexpression of miR-15a inhibited IL-1&#946;-induced expression of the Senescence Associated Secretory Phenotype &#40;SASP&#41; &#40;HMGB1 and TNF-&#945;&#41;&#44; and senescence-associated markers &#40;P21 and P16&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0003">Fig&#46; 3</a><a class="elsevierStyleCrossRef" href="#fig0003">D</a>&#8210;F&#41;&#46; SA-&#946;-Gal staining of chondrocytes also showed that the IL-1&#946;&#43;miR-15a mimic group had significantly more SA-&#946;-Gal positive cells than the IL-1&#946; stimulated group &#40;<a class="elsevierStyleCrossRef" href="#fig0003">Fig&#46; 3</a><a class="elsevierStyleCrossRef" href="#fig0003">G</a> and H&#41;&#46; Notably&#44; the inhibitory effect of miR-15a on IL-1&#946;-induced extracellular matrix reduction and senescence in chondrocytes was counteracted by overexpression of &#946;1&#44;4-GalT-I &#40;<a class="elsevierStyleCrossRef" href="#fig0003">Fig&#46; 3</a><a class="elsevierStyleCrossRef" href="#fig0003">C</a>&#8210;H&#41;&#46;</p><elsevierMultimedia ident="fig0003"></elsevierMultimedia></span><span id="sec0019" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0026">MiR-15a&#47;&#946;1&#44;4-GalT-I axis was involved in regulating NF-&#954;B signaling in IL-1&#946;-induced chondrocyte</span><p id="para0031" class="elsevierStylePara elsevierViewall">In order to find out whether or not NF-&#954;B is activated&#44; the authors observed the localization of NF-&#954;B within chondrocytes through the use of immunofluorescence staining&#46; Under IL-1&#946; stimulation&#44; NF-&#954;B was predominantly distributed in the nuclei of chondrocytes and was enhanced upon overexpression of &#946;1&#44;4-GalT-I&#46; When the miR-15a mimic was transfected into cells&#44; the activation of NF-&#954;B induced by IL-1&#946; was inhibited &#40;<a class="elsevierStyleCrossRef" href="#fig0004">Fig&#46; 4A</a>&#41;&#46; Subsequently&#44; the authors found that protein expression of both p-NF-&#954;B p65 and p-IkappaB alpha &#40;I&#954;B&#945;&#41; was significantly increased in the presence of IL-1&#946; stimulation and overexpression of &#946;1&#44;4-GalT-I&#44; compared to normal chondrocytes &#40;<a class="elsevierStyleCrossRef" href="#fig0004">Fig&#46; 4B</a>&#41;&#46; The expression of nuclear factor kappa B p65 did not differ significantly across the groups &#40;<a class="elsevierStyleCrossRef" href="#fig0004">Fig&#46; 4B</a>&#41;&#46; Next&#44; NF-&#954;B promoter activity was assessed by the luciferase reporter system&#46; The results showed a significant increase in NF-&#954;B promoter activity in chondrocytes under IL-1&#946; stimulation&#44; and a further increase when combined with &#946;1&#44;4-GalT-I overexpression &#40;<a class="elsevierStyleCrossRef" href="#fig0004">Fig&#46; 4C</a>&#41;&#46; Meanwhile&#44; the transfection of miR-15a mimic effectively blocked the increased NF-&#954;B promoter activity induced by IL-1&#946;&#44; which was reversed by the co-transfection with &#946;1&#44;4-GalT-I overexpression &#40;<a class="elsevierStyleCrossRef" href="#fig0004">Fig&#46; 4C</a>&#41;&#46;</p><elsevierMultimedia ident="fig0004"></elsevierMultimedia></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0027">Intra-articular Injection of miR-15a ameliorates cartilage degeneration by inhibiting &#946;1&#44;4-GalT-I&#47;NF-&#954;B</span><p id="para0032" class="elsevierStylePara elsevierViewall">To observe the effect of miR-15a on articular cartilage degeneration <span class="elsevierStyleItalic">in vivo</span>&#44; the authors constructed DMM-induced OA mice and performed intra-articular injections of Lv-miR-15a one week after surgery &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 5A</a>&#41;&#46; The authors found that intra-articular injection of Lv-miR-15a in DMM-induced OA mice significantly reduced OARSI scores &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 5B</a>&#44; <a class="elsevierStyleCrossRef" href="#fig0005">p</a> &#60; 0&#46;001&#41; and inhibited mRNA expression of &#946;1&#44;4-GalT-I in articular cartilage &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 5C</a>&#44; <a class="elsevierStyleCrossRef" href="#fig0005">p</a> &#60; 0&#46;05&#41;&#44; compared to the DMM-induced OA mice group&#46; The H&#38;E staining and safranin O-fast green staining of the joints showed that the destruction and degeneration of articular cartilage in DMM-induced OA mice were significantly inhibited after intra-articular injection of Lv-miR-15a &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 5</a>&#41;&#46; Consistent with the <span class="elsevierStyleItalic">in vitro</span> IL-1&#946; stimulation of chondrocytes&#44; p-NF-&#954;B p65 was significantly increased in DMM-induced OA mice&#44; which was reversed by intra-articular injection of Lv-miR-15a &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 5F</a>&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span></span><span id="sec0021" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0028">Discussion</span><p id="para0033" class="elsevierStylePara elsevierViewall">In OA&#44; the function and mechanism of &#946;1&#44;4-GalT-I in cartilage degeneration are poorly understood&#46; The authors simulated the damage of OA by constructing a microsurgery-induced OA model and an <span class="elsevierStyleItalic">in vitro</span> chondrocyte model&#46; Compared to controls&#44; the authors found that &#946;1&#44; 4-GalT-I was upregulated in articular cartilage and IL-1&#946;-stimulated chondrocytes&#44; while the opposite was observed for miR-15a&#46; In IL-1&#946;-stimulated chondrocytes&#44; &#946;1&#44;4-GalT-I promoted extracellular matrix degradation&#44; senescence&#44; and NF-&#954;B activation&#44; which could be reversed by overexpression of miR-15a&#46; Regarding mechanism&#44; miR-15a inhibited &#946;1&#44;4-GalT-I mRNA translation&#46; Intra-articular injections of miR-15a could reduce cartilage degeneration by inhibiting &#946;1&#44;4-GalT-I and NF-&#954;B activation <span class="elsevierStyleItalic">in vivo</span>&#46; MiR-15a and &#946;1&#44;4-GalT-I could be potential targets for the treatment of OA in the future&#46;</p><p id="para0034" class="elsevierStylePara elsevierViewall">According to proteomic studies&#44; the endoplasmic reticulum of aging chondrocytes undergoes excessive sulfur oxidation&#44; resulting in an inflammatory response&#46;<a class="elsevierStyleCrossRef" href="#bib0022"><span class="elsevierStyleSup">22</span></a> Similar to the previous study&#44;<a class="elsevierStyleCrossRef" href="#bib0006"><span class="elsevierStyleSup">6</span></a> the present data showed that both the mRNA and protein expression levels of &#946;1&#44;4-GalT-I in the OA mouse model were significantly higher than those in the control&#46; To uncover the potential miRNAs targeting &#946;1&#44;4-GalT-I in OA&#44; TargetScan was applied to predict a list of miRNAs based on &#946;1&#44;4-GalT-I as the target mRNA&#46; Among all predicted miRNAs&#44; five miRNAs&#44; which included miR-146a&#44; miR-15a&#44; miR-140&#44; miR-26&#44; and miR-9&#44; were selected for further verification of the interaction with &#946;1&#44;4-GalT-I as they have been implicated in OA progression in previous reports&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">15</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRefs" href="#bib0023"><span class="elsevierStyleSup">23&#8211;26</span></a> Except for miR-9&#44; the other four miRNAs significantly down-regulated in the OA model&#46; More importantly&#44; the present study found that the expression miR-15a and miR-26 displayed a negative correlation with &#946;1&#44;4-GalT-I expression in OA&#46; Since the miR-15a with &#946;1&#44;4-GalT-I displayed the strongest correlation&#44; miR-15a was chosen for further study&#46;</p><p id="para0035" class="elsevierStylePara elsevierViewall">It has been reported that <span class="elsevierStyleItalic">in vitro</span> IL-1&#946; stimulation of chondrocytes induced high &#946;1&#44;4-GalT-I&#39;s expression as well as simultaneously inflammation in chondrocytes&#46;<a class="elsevierStyleCrossRef" href="#bib0027"><span class="elsevierStyleSup">27</span></a> Furthermore&#44; IL-1&#946; stimulated endoplasmic reticulum stress and the NLRP3 inflammasome in chondrocytes&#46;<a class="elsevierStyleCrossRef" href="#bib0028"><span class="elsevierStyleSup">28</span></a> In chondrocytes&#44; both IL-1&#946; and TNF-&#945; can activate the NF-kB signaling&#44; and lead to the production of IL-6&#44; IL-1&#946;&#44; and TNF-&#945;&#44; and&#44; most notably&#44; apoptosis of chondrocytes&#46;<a class="elsevierStyleCrossRef" href="#bib0029"><span class="elsevierStyleSup">29</span></a> Therefore&#44; the present present study utilized IL-1&#946; to stimulate chondrocytes <span class="elsevierStyleItalic">in vitro</span>&#46;</p><p id="para0036" class="elsevierStylePara elsevierViewall">Previous studies have identified multiple mechanisms involved in chondrocyte reduction in OA&#44; including apoptosis&#44; autophagy&#44; ferroptosis&#44; and senescence&#46;<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">30&#8211;33</span></a> For example&#44; mechanical overloading induces ferroptosis of chondrocytes through the Piezo1 channel of calcium inward flow&#46;<a class="elsevierStyleCrossRef" href="#bib0001"><span class="elsevierStyleSup">1</span></a> Overexpression of circular RNAs forkhead box O3 promotes extracellular matrix synthesis and reduces chondrocyte apoptosis by inhibiting the PI3K&#47;AKT signaling pathway&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">30</span></a><a class="elsevierStyleCrossRef" href="#bib0034"><span class="elsevierStyleSup">34</span></a> E3-ubiquitin ligase HECTD1&#44; regulates chondrocyte autophagy by ubiquitinating Rubicon at lysine residue 534&#46;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">35</span></a> &#946;1&#44;4-GalT-I protects chondrocytes from apoptosis induced by TNF-&#945;&#44; effectively&#46;<a class="elsevierStyleCrossRef" href="#bib0007"><span class="elsevierStyleSup">7</span></a> MiR-15a was confirmed to inhibit TLR4&#47;NF-&#954;B signaling to effectively reduce the dysfunction of chondrocytes&#46;<a class="elsevierStyleCrossRef" href="#bib0036"><span class="elsevierStyleSup">36</span></a> The findings of the latest investigation demonstrated that NF-&#954;B was inhibited by miR-15a&#44; hence inhibiting chondrocyte senescence&#46;<a class="elsevierStyleCrossRef" href="#bib0037"><span class="elsevierStyleSup">37</span></a> Here&#44; the authors demonstrated that &#946;1&#44;4-GalT-I stimulates NF-&#954;B and I&#954;B&#945; phosphorylation&#44; which in turn causes extracellular matrix degradation and chondrocyte senescence&#46; The present research suggests that the miR-15a may inhibit chondrocyte senescence&#46; In addition&#44; the mechanism by which the miR-15a&#47;&#946;1&#44;4-GalT-I axis regulates chondrocyte senescence has never been studied&#46; According to the results of the present research&#44; &#946;1&#44;4-GalT-I drives cellular senescence in chondrocytes via activating the transcription factor NF-&#954;B&#44; and miR-15a can reverse this effect&#46; This is a novel mechanism by which miR-15a and &#946;1&#44;4-GalT-I contribute to OA&#46;</p><p id="para0037" class="elsevierStylePara elsevierViewall">Notably&#44; miR-15a expression in OA articular cartilage tended to be low compared to healthy controls&#46;<a class="elsevierStyleCrossRef" href="#bib0026"><span class="elsevierStyleSup">26</span></a><a class="elsevierStyleCrossRef" href="#bib0038"><span class="elsevierStyleSup">38</span></a> Studies have shown that miR-15a promotes the polymerization of proteoglycan and collagen by targeting the ADAMTS5 gene 3&#8242;-UTR in the articular cartilage of OA patients &#40;Grade III&#8210;IV&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0026"><span class="elsevierStyleSup">26</span></a> However&#44; it has also been shown that miR-15a expression is elevated in articular cartilage and promotes extracellular matrix degradation in chondrocytes by inhibiting vascular endothelial growth factor a&#46;<a class="elsevierStyleCrossRef" href="#bib0039"><span class="elsevierStyleSup">39</span></a> Furthermore&#44; miR-15a accelerates chondrocyte degeneration by inhibiting Parathyroid hormone-related protein&#46;<a class="elsevierStyleCrossRef" href="#bib0038"><span class="elsevierStyleSup">38</span></a></p><p id="para0038" class="elsevierStylePara elsevierViewall">Here&#44; from animal studies&#44; microsurgery-induced OA would be classified as an acute injury-induced inflammation&#46; In contrast&#44; clinical patients with OA and the specimens obtained are mostly in a chronic inflammatory state&#46; The authors speculate that miR-15a and &#946;1&#44;4-GalT-I possess pro-inflammatory or anti-inflammatory effects on chondrocytes at different times of the inflammatory response in OA&#46; In articular cartilage of microsurgery-induced acute injurious OA&#44; miR-15a was low expressed and &#946;1&#44;4-GalT-I were high&#46;<a class="elsevierStyleCrossRef" href="#bib0009"><span class="elsevierStyleSup">9</span></a> At this point&#44; miR-15a protected chondrocytes from inflammation-induced senescence and damage&#44; whereas &#946;1&#44;4-GalT-I instead promoted chondrocyte senescence and inflammatory responses&#46; When OA progresses to the chronic inflammatory &#40;Grade III&#8210;IV&#41; stage&#44; miR-15a promotes the degeneration of chondrocytes by inhibiting parathyroid hormone-related protein&#46;<a class="elsevierStyleCrossRef" href="#bib0038"><span class="elsevierStyleSup">38</span></a> And&#44; &#946;1&#44;4-GalT-I&#39;s overexpression will activate the MAP Kinase signal pathway&#44; which would then lead to autocrine production of TNF-&#945;&#44; thereby exacerbating the inflammatory response&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">40</span></a> As in previous studies&#44; cyclic AMP-responsive element-binding protein H&#44; a regulator of the inflammatory response&#44; was found to have anti-inflammatory capacity during acute injury and pro-inflammatory response during chronic inflammation&#46;<a class="elsevierStyleCrossRef" href="#bib0041"><span class="elsevierStyleSup">41</span></a> However&#44; considering that the regulatory mechanisms within chondrocytes are complex&#44; this speculation requires further validation at a later stage&#46;</p><p id="para0039" class="elsevierStylePara elsevierViewall">Even though the authors have found the functionality of &#946;1&#44;4-GalT-I and miR-15a presenting to surgery-induced OA as well as the molecular mechanism behind it&#44; more research is still required&#46; Despite this fact&#44; there are certain limitations to this research&#46; First&#44; the processes that underlie the downregulation of miR-15a in OA chondrocytes remain unclear&#46; Besides&#44; the potential correlation between miR-26 and &#946;1&#44;4-GalT-I has also been uncovered in the present study&#44; but further verification and analysis is required to perform in future study&#46;</p><p id="para0040" class="elsevierStylePara elsevierViewall">In conclusion&#44; the present research showed that miR-15a and &#946;1&#44;4-GalT-I are&#44; respectively&#44; down-regulated&#44; and up-regulated in the cartilage from the OA model&#46; The miR-15a was able to suppress the production of &#946;1&#44;4-GalT-I because it bound to its 3&#8242;UTR&#46; Moreover&#44; &#946;1&#44;4-GalT-I caused degradation of cartilage as well as chondrocyte senescence by increasing phosphorylation of NF-&#954;B&#44; and miR-15a was able to mitigate these negative effects by acting as an antagonist&#46; In future diagnostic and therapeutic targets for OA&#44; the miR-15a&#47;&#946;1&#44;4-GalT-I axis may be included&#46;</p></span><span id="sec0022" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0029">Funding</span><p id="para0042" class="elsevierStylePara elsevierViewall">This work was supported by the <span class="elsevierStyleGrantSponsor" id="gs0001">Medical Research Project of Jiangsu Provincial Health Commission</span> &#40;grant number <span class="elsevierStyleGrantNumber" refid="gs0001">M2020061</span>&#41;&#59; <span class="elsevierStyleGrantSponsor" id="gs0002">Yancheng Medical Science and Technology Development Program</span> &#40;grant number <span class="elsevierStyleGrantNumber" refid="gs0002">YK2019067</span>&#41; and <span class="elsevierStyleGrantSponsor" id="gs0003">Research Project of Jianhu Clinical College&#44; Jiangsu Vocational College of Medicine</span> &#40;grant number <span class="elsevierStyleGrantNumber" refid="gs0003">20229JH09</span>&#41;&#46;</p></span><span id="sec0022a" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0029a">CRediT authorship contribution statement</span><p id="para0042a" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Hairong Wang&#58;</span> Conceptualization&#44; Data curation&#44; Formal analysis&#44; Writing &#8211; original draft&#44; Writing &#8211; review &#38; editing&#46; <span class="elsevierStyleBold">Weilin Wang&#58;</span> Data curation&#44; Formal analysis&#44; Investigation&#46; <span class="elsevierStyleBold">Jian Wang&#58;</span> Conceptualization&#44; Formal analysis&#44; Methodology&#46; <span class="elsevierStyleBold">Linsheng Zhang&#58;</span> Data curation&#44; Formal analysis&#46; <span class="elsevierStyleBold">Yujie Luo&#58;</span> Data curation&#44; Formal analysis&#46; <span class="elsevierStyleBold">Xiaobo Tang&#58;</span> Data curation&#44; Formal analysis&#44; Funding acquisition&#44; Methodology&#46;</p></span></span>"
    "textoCompletoSecciones" => array:1 [
      "secciones" => array:11 [
        0 => array:3 [
          "identificador" => "xres2232195"
          "titulo" => "Highlights"
          "secciones" => array:1 [
            0 => array:1 [
              "identificador" => "abss0001"
            ]
          ]
        ]
        1 => array:3 [
          "identificador" => "xres2232194"
          "titulo" => "Abstract"
          "secciones" => array:4 [
            0 => array:2 [
              "identificador" => "abss0002"
              "titulo" => "Objective"
            ]
            1 => array:2 [
              "identificador" => "abss0003"
              "titulo" => "Methods"
            ]
            2 => array:2 [
              "identificador" => "abss0004"
              "titulo" => "Results"
            ]
            3 => array:2 [
              "identificador" => "abss0005"
              "titulo" => "Conclusion"
            ]
          ]
        ]
        2 => array:2 [
          "identificador" => "xpalclavsec1869036"
          "titulo" => "Keywords"
        ]
        3 => array:2 [
          "identificador" => "sec0001"
          "titulo" => "Introduction"
        ]
        4 => array:3 [
          "identificador" => "sec0002"
          "titulo" => "Materials &#38; methods"
          "secciones" => array:12 [
            0 => array:2 [
              "identificador" => "sec0003"
              "titulo" => "Animal model establishment and intervention"
            ]
            1 => array:2 [
              "identificador" => "sec0004"
              "titulo" => "Cell culture and treatment in vitro"
            ]
            2 => array:2 [
              "identificador" => "sec0005"
              "titulo" => "Transfection"
            ]
            3 => array:2 [
              "identificador" => "sec0006"
              "titulo" => "Histopathological analysis"
            ]
            4 => array:2 [
              "identificador" => "sec0007"
              "titulo" => "Quantitative real-time polymerase chain reaction &#40;qPCR&#41;"
            ]
            5 => array:2 [
              "identificador" => "sec0008"
              "titulo" => "Western blot"
            ]
            6 => array:2 [
              "identificador" => "sec0009"
              "titulo" => "Prediction of target sites by TargetScan"
            ]
            7 => array:2 [
              "identificador" => "sec0010"
              "titulo" => "Dual-luciferase constructs and reporter assay"
            ]
            8 => array:2 [
              "identificador" => "sec0011"
              "titulo" => "Enzyme-linked immunosorbent assays &#40;ELISA&#41;"
            ]
            9 => array:2 [
              "identificador" => "sec0012"
              "titulo" => "Assay of senescence-associated &#946;-galactosidase &#40;SA-&#946;-Gal&#41; activity"
            ]
            10 => array:2 [
              "identificador" => "sec0013"
              "titulo" => "Immunofluorescence"
            ]
            11 => array:2 [
              "identificador" => "sec0014"
              "titulo" => "Statistical analysis"
            ]
          ]
        ]
        5 => array:3 [
          "identificador" => "sec0015"
          "titulo" => "Results"
          "secciones" => array:5 [
            0 => array:2 [
              "identificador" => "sec0016"
              "titulo" => "Expression of &#946;1&#44;4-GalT-I is elevated in the articular cartilage of DMM-induced OA mice"
            ]
            1 => array:2 [
              "identificador" => "sec0017"
              "titulo" => "MicroRNA-15a is down-regulated and negatively correlated with &#946;1&#44;4-GalT-I in articular cartilage of DMM-induced OA mice"
            ]
            2 => array:2 [
              "identificador" => "sec0018"
              "titulo" => "MiR-15a alleviated ECM degradation and cellular senescence in IL-1&#946;-induced chondrocytes by suppressing &#946;1&#44;4-GalT-I"
            ]
            3 => array:2 [
              "identificador" => "sec0019"
              "titulo" => "MiR-15a&#47;&#946;1&#44;4-GalT-I axis was involved in regulating NF-&#954;B signaling in IL-1&#946;-induced chondrocyte"
            ]
            4 => array:2 [
              "identificador" => "sec0020"
              "titulo" => "Intra-articular Injection of miR-15a ameliorates cartilage degeneration by inhibiting &#946;1&#44;4-GalT-I&#47;NF-&#954;B"
            ]
          ]
        ]
        6 => array:2 [
          "identificador" => "sec0021"
          "titulo" => "Discussion"
        ]
        7 => array:2 [
          "identificador" => "sec0022"
          "titulo" => "Funding"
        ]
        8 => array:2 [
          "identificador" => "sec0022a"
          "titulo" => "CRediT authorship contribution statement"
        ]
        9 => array:2 [
          "identificador" => "xack769798"
          "titulo" => "Acknowledgments"
        ]
        10 => array:1 [
          "titulo" => "References"
        ]
      ]
    ]
    "pdfFichero" => "main.pdf"
    "tienePdf" => true
    "fechaRecibido" => "2023-02-27"
    "fechaAceptado" => "2023-07-03"
    "PalabrasClave" => array:1 [
      "en" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec1869036"
          "palabras" => array:5 [
            0 => "MicroRNA-15a"
            1 => "&#946;1&#44;4-GalT-I"
            2 => "Cartilage degeneration"
            3 => "NF-&#954;B"
            4 => "Osteoarthritis"
          ]
        ]
      ]
    ]
    "tieneResumen" => true
    "highlights" => array:2 [
      "titulo" => "Highlights"
      "resumen" => "<span id="abss0001" class="elsevierStyleSection elsevierViewall"><p id="spara006" class="elsevierStyleSimplePara elsevierViewall"><ul class="elsevierStyleList" id="celist0001"><li class="elsevierStyleListItem" id="celistitem0001"><span class="elsevierStyleLabel">&#8226;</span><p id="para0001" class="elsevierStylePara elsevierViewall">MiR-15a&#47;&#946;1&#44;4-GalT-I axis inhibits ECM degradation and senescence in chondrocytes&#46;</p></li><li class="elsevierStyleListItem" id="celistitem0002"><span class="elsevierStyleLabel">&#8226;</span><p id="para0002" class="elsevierStylePara elsevierViewall">MiR-15a inhibits &#946;1&#44;4-GalT-I expression with post-transcriptional modifications&#46;</p></li><li class="elsevierStyleListItem" id="celistitem0003"><span class="elsevierStyleLabel">&#8226;</span><p id="para0003" class="elsevierStylePara elsevierViewall">&#946;1&#44;4-GalT-I promotes NF-&#954;B phosphorylation to exacerbate osteoarthritis&#46;</p></li><li class="elsevierStyleListItem" id="celistitem0004"><span class="elsevierStyleLabel">&#8226;</span><p id="para0004" class="elsevierStylePara elsevierViewall">Intra-articular injection of miR-15a attenuates cartilage degeneration <span class="elsevierStyleItalic">in vivo</span>&#46;</p></li></ul></p></span>"
    ]
    "resumen" => array:1 [
      "en" => array:3 [
        "titulo" => "Abstract"
        "resumen" => "<span id="abss0002" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0003">Objective</span><p id="spara007" class="elsevierStyleSimplePara elsevierViewall">Osteoarthritis is a condition characterized by articular cartilage degradation&#46; The increased expression of &#946;1&#44;4-Galactosyltransferase-I &#40;&#946;1&#44;4-GalT-I&#41; in the articular cartilage of osteoarthritis patients was related to an inflammatory response&#46; The aim of this study was to elucidate the role of &#946;1&#44;4-GalT-I in osteoarthritis&#46; This study aimed to determine the function of 1&#44;4-GalT-I in osteoarthritis&#46;</p></span> <span id="abss0003" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0004">Methods</span><p id="spara008" class="elsevierStyleSimplePara elsevierViewall">The osteoarthritis mouse model with the destabilization of the medial meniscus was established by microsurgical technique&#46; Pathological changes in articular cartilage were observed by hematoxylin and eosin staining and safranin O-fast green staining&#46; Quantitative real-time polymerase chain reaction&#44; western blot&#44; and enzyme-linked immunosorbent assays were used to observe mRNA and protein expression&#44; respectively&#46; RNA interactions were verified by a luciferase reporter assay&#46; SA-&#946;-Gal staining was used to assess chondrocyte senescence&#46; Immunofluorescence staining was conducted to observe the localization of Nuclear Factor-kappaB &#40;NF-&#954;B&#41;&#46;</p></span> <span id="abss0004" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0005">Results</span><p id="spara009" class="elsevierStyleSimplePara elsevierViewall">&#946;1&#44;4-GalT-I and microRNA-15a &#40;miR-15a&#41; show high and low expression in the articular cartilage of osteoarthritis&#44; respectively&#46; MiR-15a inhibits the mRNA translation of &#946;1&#44;4-GalT-I&#46; &#946;1&#44;4-GalT-I promotes extracellular matrix degradation&#44; senescence&#44; and NF-&#954;B activation in IL-1&#946;-stimulated chondrocytes&#44; which can be reversed by overexpression of miR-15a&#46; Intra-articular injection of microRNA-15a ameliorates cartilage degeneration by inhibiting &#946;1&#44;4-GalT-I and phosphorylation of NF-&#954;B <span class="elsevierStyleItalic">in vivo</span>&#46;</p></span> <span id="abss0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0006">Conclusion</span><p id="spara010" class="elsevierStyleSimplePara elsevierViewall">The authors clarified that the miR-15a&#47;&#946;1&#44;4-GalT-I axis inhibits the phosphorylation of NF-&#954;B thereby inhibiting extracellular matrix degradation and senescence in chondrocytes to alleviate cartilage degeneration in osteoarthritis&#46; MiR-15a and &#946;1&#44;4-GalT-I may serve as potentially effective targets for the future treatment of osteoarthritis&#46;</p></span>"
        "secciones" => array:4 [
          0 => array:2 [
            "identificador" => "abss0002"
            "titulo" => "Objective"
          ]
          1 => array:2 [
            "identificador" => "abss0003"
            "titulo" => "Methods"
          ]
          2 => array:2 [
            "identificador" => "abss0004"
            "titulo" => "Results"
          ]
          3 => array:2 [
            "identificador" => "abss0005"
            "titulo" => "Conclusion"
          ]
        ]
      ]
    ]
    "apendice" => array:1 [
      0 => array:1 [
        "seccion" => array:1 [
          0 => array:4 [
            "apendice" => "<p id="para0041a" class="elsevierStylePara elsevierViewall"><elsevierMultimedia ident="ecom0001"></elsevierMultimedia></p>"
            "etiqueta" => "Appendix"
            "titulo" => "Supplementary materials"
            "identificador" => "sec0024"
          ]
        ]
      ]
    ]
    "multimedia" => array:6 [
      0 => array:8 [
        "identificador" => "fig0001"
        "etiqueta" => "Fig&#46; 1"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr1.jpeg"
            "Alto" => 1630
            "Ancho" => 2833
            "Tamanyo" => 522235
          ]
        ]
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "alt0001"
            "detalle" => "Fig "
            "rol" => "short"
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spara001" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Expression of &#946;1&#44;4-GalT-I is elevated in the articular cartilage of DMM-induced OA mice</span>&#46; The mice were randomly assigned to a DMM group and a Sham group&#44; with six mice in each group&#46; &#40;A and B&#41; Representative images of articular cartilage stained with H&#38;E &#40;A&#41; and safranin O-fast green &#40;B&#41; &#40;scale bar&#58; 100 &#956;m&#41;&#46; &#40;C&#41; OARSI score of the joints&#46; &#40;D and E&#41; The qPCR and western blot were used to detect mRNA and protein expression of &#946;1&#44;4-GalT-I in articular cartilage &#40;&#42;&#42;&#42; p &#60; 0&#46;001&#44; &#42;&#42; p &#60; 0&#46;01&#41;&#46;</p>"
        ]
      ]
      1 => array:8 [
        "identificador" => "fig0002"
        "etiqueta" => "Fig&#46; 2"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr2.jpeg"
            "Alto" => 3754
            "Ancho" => 3583
            "Tamanyo" => 713724
          ]
        ]
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "alt0002"
            "detalle" => "Fig "
            "rol" => "short"
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spara002" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">MiR-15a-5p is down-regulated and negatively correlated with &#946;1&#44;4-GalT-I in articular cartilage of DMM-induced OA mice</span>&#46; &#40;A&#8210;E&#41; The expression of miR-146a&#44; miR-15a&#44; miR-140&#44; miR-26a&#44; and miR-9 in articular cartilage were detected by qPCR&#46; &#40;F&#8210;J&#41; Pearson correlation coefficient was performed to analyze the correlation of miR-146a&#44; miR-15a&#44; miR-140&#44; miR-26a&#44; and miR-9 with the expression of &#946;1&#44;4-GalT-I&#46; &#40;K&#41; The detection of miR-15a in chondrocytes by qPCR to validate the efficiency of Lipofectamine 3000 transfection of miR-15a mimics into chondrocytes&#46; &#40;L&#41; Prediction of miR-15a targeting sites with mRNA of &#946;1&#44;4-GalT-I by TargetScan&#46; &#40;M&#41; The luciferase reporter assay was conducted to validate the relationship of miR-15a with &#946;1&#44;4-GalT-I&#46; &#40;N&#8210;O&#41; The qPCR and western blot were executed to detect mRNA and protein expression of &#946;1&#44;4-GalT-I in chondrocytes after being transfected with miR-15a mimic&#44; respectively &#40;&#42; p &#60; 0&#46;05&#44; &#42;&#42; p &#60; 0&#46;01&#41;&#46;</p>"
        ]
      ]
      2 => array:8 [
        "identificador" => "fig0003"
        "etiqueta" => "Fig&#46; 3"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr3.jpeg"
            "Alto" => 3382
            "Ancho" => 3583
            "Tamanyo" => 1183332
          ]
        ]
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "alt0003"
            "detalle" => "Fig "
            "rol" => "short"
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spara003" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">MiR-15a alleviated ECM degradation and cellular senescence in chondrocytes by suppressing &#946;1&#44;4-GalT-I</span>&#46; To mimic chondrocytes in OA&#44; the authors stimulated human chondrocytes in vitro with IL-1 &#40;10 ng&#47;mL&#41;&#46; The effects of miR-15a and &#946;1&#44;4-GalT-I on extracellular matrix degradation and senescence in chondrocytes was investigated&#46; Chondrocytes <span class="elsevierStyleItalic">in vitro</span> were divided into five groups&#58; IL-1&#946; stimulation group&#44; miR-15a mimic&#160;&#43;&#160;IL-1&#946; group&#44; &#946;1&#44;4-GalT-I overexpression &#40;OE&#41;&#160;&#43;&#160;IL-1&#946; group&#44; miR-15a mimic&#160;&#43;&#160;&#946;1&#44;4-GalT-I OE&#160;&#43;&#160;IL-1&#946; group&#44; and control group&#46; &#40;A and B&#41; The authors observed changes in the expression of miR-15a and &#946;1&#44;4-GalT-I at different stimulation times &#40;0h&#44; 6h&#44; 12h&#44; 24h&#44; and 48h&#41; by qPCR or western blot&#44; respectively &#40;as compared to 0h&#44; &#42; p &#60; 0&#46;05&#44; &#42;&#42;&#42; p &#60; 0&#46;001&#41;&#46; &#40;C&#41; Western blot was used to detect the protein expression of &#946;1&#44;4-GalT-I&#44; aggrecan&#44; Collange II and ADAMTS5&#46; &#40;D&#8210;E&#41; The Senescence-Associated Secretory Phenotype &#40;SASP&#41;&#44; Tumor Necrosis Factor-alpha &#40;TNF-&#945;&#41; and High Mobility Group Box 1 &#40;HMGB1&#41; were detected using ELISA &#40;&#42;&#42;&#42; p &#60; 0&#46;001&#44; as compared to control group&#59; &#35;&#35;&#35; p &#60; 0&#46;001&#44; as compared to IL-1&#946; group&#59; &#36;&#36; p &#60; 0&#46;01&#44; &#36;&#36;&#36; p &#60; 0&#46;001&#44; as compared to IL-1&#946; group&#41;&#46; &#40;F&#41; Senescence-related markers &#40;P21 and P16&#41; were detected by western blot&#46; &#40;G&#8210;H&#41; The SA-&#946;-Gal staining of chondrocytes &#40;Scale bar&#58; 100 &#956;m&#41; &#40;&#42;&#42; p &#60; 0&#46;01&#44; as compared with control group&#59; &#35;&#35; p &#60; 0&#46;01&#44; &#35;&#35;&#35; p &#60; 0&#46;001&#44; as compared with IL-1&#946; group&#59; &#36; p &#60; 0&#46;05&#44; as compared with IL-1&#946;&#160;&#43;&#160;miR-15a mimic group&#41;&#46;</p>"
        ]
      ]
      3 => array:8 [
        "identificador" => "fig0004"
        "etiqueta" => "Fig&#46; 4"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr4.jpeg"
            "Alto" => 3123
            "Ancho" => 3583
            "Tamanyo" => 1151685
          ]
        ]
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "alt0004"
            "detalle" => "Fig "
            "rol" => "short"
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spara004" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">MiR-15a&#47;&#946;1&#44;4-GalT-I axis was involved in regulating NF-&#954;B signaling in IL-1&#946;-induced chondrocyte</span>&#46; Chondrocytes cultured in vitro were divided into four groups&#58; IL-1&#946; group&#44; miR-15a mimic&#160;&#43;&#160;IL-1&#946; group&#44; &#946;1&#44;4-GalT-I OE&#160;&#43;&#160;IL-1&#946; group&#44; and miR-15a mimic&#160;&#43;&#160;&#946;1&#44;4-GalT-I OE&#160;&#43;&#160;IL-1&#946; group &#40;n&#160;&#61;&#160;3&#41;&#46; &#40;A&#41; The representative images demonstrating the NF-&#954;B in chondrocytes as stained by immunofluorescence&#46; When NF-&#954;B is not activated&#44; it is mainly distributed in the cytoplasm and&#44; when activated&#44; in the nucleus&#46; DAPI shows the location of the nucleus &#40;Scale bar&#58; 100 &#956;m&#41;&#46; &#40;B&#41; Western blot was conducted to detect the expression of I&#954;B&#945;&#44; p-I&#954;B&#945;&#44; p-NF-&#954;B p65&#44; and NF-&#954;B p65&#46; &#40;C&#41; The luciferase reporter assay was conducted to detect activity of NF-&#954;B promoter &#40;&#42;&#42;&#42; p &#60; 0&#46;01&#44; as compared with the control group&#59; &#35;&#35;&#35; p &#60; 0&#46;001&#44; &#35; p &#60; 0&#46;05&#44; as compared with the IL-1&#946; group&#59; &#36;&#36;&#36; p &#60; 0&#46;001&#44; as compared with the IL-1&#946;&#160;&#43;&#160;miR-15a mimic group&#41;&#46;</p>"
        ]
      ]
      4 => array:8 [
        "identificador" => "fig0005"
        "etiqueta" => "Fig&#46; 5"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr5.jpeg"
            "Alto" => 3696
            "Ancho" => 3583
            "Tamanyo" => 1427181
          ]
        ]
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "alt0005"
            "detalle" => "Fig "
            "rol" => "short"
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spara005" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Intra-Articular Injection &#40;IAJ&#41; of miR-15a ameliorates cartilage degeneration by inhibiting &#946;1&#44;4-GalT-I&#47;NF-&#922;b</span>&#46; &#40;A&#41; Experimental layout to observe the effect of miR-15a on cartilage degeneration in vivo&#46; Mice were divided into the Sham&#44; DMM&#44; DMM&#160;&#43;&#160;Lv-NC&#44; and DMM&#160;&#43;&#160;Lv-miR-15a groups&#46; The authors established DMM-induced OA mice by microsurgery and administered intra-articular injections of Lv-miR-15a once daily for 7 weeks&#44; one week after surgery&#46; &#40;B&#41; OARSI scores of the joints in each group&#46; &#40;C&#41; The mRNA expression of &#946;1&#44;4-GalT-I in articular cartilage&#44; which was detected by qPCR&#46; &#40;D and E&#41; The H&#38;E staining &#40;D&#41; and the safranin O-fast green staining &#40;E&#41; both showed that the articular cartilage in the knee of the mouse had undergone morphological changes &#40;Scale bar&#160;&#61;&#160;100 &#956;m&#41;&#46; &#40;F&#41; The NF-&#954;B p65 and p-NF-&#954;B p65 expression in articular cartilage were detected by western blot &#40;&#35; p &#60; 0&#46;05&#44; &#35;&#35;&#35; p &#60; 0&#46;001&#44; as compared to DMM group&#59; &#42;&#42;&#42; p &#60; 0&#46;001&#44; as compared to Sham group&#41;&#46;</p>"
        ]
      ]
      5 => array:6 [
        "identificador" => "ecom0001"
        "tipo" => "MULTIMEDIAECOMPONENTE"
        "mostrarFloat" => false
        "mostrarDisplay" => true
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "alt0006"
            "detalle" => "Image&#44; application "
            "rol" => "short"
          ]
        ]
        "Ecomponente" => array:2 [
          "fichero" => "mmc1.docx"
          "ficheroTamanyo" => 21865
        ]
      ]
    ]
    "bibliografia" => array:2 [
      "titulo" => "References"
      "seccion" => array:1 [
        0 => array:2 [
          "identificador" => "cebibsec1"
          "bibliografiaReferencia" => array:41 [
            0 => array:3 [
              "identificador" => "bib0001"
              "etiqueta" => "1"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Mechanical overloading induces GPX4-regulated chondrocyte ferroptosis in osteoarthritis via Piezo1 channel facilitated calcium influx"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "S&#46; Wang"
                            1 => "W&#46; Li"
                            2 => "P&#46; Zhang"
                            3 => "Z&#46; Wang"
                            4 => "X&#46; Ma"
                            5 => "C&#46; Liu"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.jare.2022.01.004"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Adv Res"
                        "fecha" => "2022"
                        "volumen" => "41"
                        "paginaInicial" => "63"
                        "paginaFinal" => "75"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/36328754"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            1 => array:3 [
              "identificador" => "bib0002"
              "etiqueta" => "2"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Chondrocyte dedifferentiation and osteoarthritis &#40;OA&#41;"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "E&#46; Charlier"
                            1 => "C&#46; Deroyer"
                            2 => "F&#46; Ciregia"
                            3 => "O&#46; Malaise"
                            4 => "S&#46; Neuville"
                            5 => "Z&#46; Plener"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.bcp.2019.02.036"
                      "Revista" => array:6 [
                        "tituloSerie" => "Biochem Pharmacol"
                        "fecha" => "2019"
                        "volumen" => "165"
                        "paginaInicial" => "49"
                        "paginaFinal" => "65"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/30853397"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            2 => array:3 [
              "identificador" => "bib0003"
              "etiqueta" => "3"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Epigenetics and osteoarthritis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "M&#46; Zhang"
                            1 => "J&#46; Wang"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.gendis.2014.12.005"
                      "Revista" => array:7 [
                        "tituloSerie" => "Genes Dis"
                        "fecha" => "2015"
                        "volumen" => "2"
                        "numero" => "1"
                        "paginaInicial" => "69"
                        "paginaFinal" => "75"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25961070"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            3 => array:3 [
              "identificador" => "bib0004"
              "etiqueta" => "4"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The role of metabolism in chondrocyte dysfunction and the progression of osteoarthritis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "L&#46; Zheng"
                            1 => "Z&#46; Zhang"
                            2 => "P&#46; Sheng"
                            3 => "A&#46; Mobasheri"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:3 [
                        "tituloSerie" => "Ageing Res Rev"
                        "fecha" => "2021"
                        "volumen" => "66"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            4 => array:3 [
              "identificador" => "bib0005"
              "etiqueta" => "5"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Mice overexpressing &#946;-1&#44;4-Galactosyltransferase I are resistant to TNF-induced inflammation and DSS-induced colitis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "V&#46; Vanhooren"
                            1 => "R&#46;E&#46; Vandenbroucke"
                            2 => "S&#46; Dewaele"
                            3 => "E&#46; Van Hamme"
                            4 => "J&#46;J&#46; Haigh"
                            5 => "T&#46; Hochepied"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1371/journal.pone.0079883"
                      "Revista" => array:6 [
                        "tituloSerie" => "PloS One"
                        "fecha" => "2013"
                        "volumen" => "8"
                        "numero" => "12"
                        "paginaInicial" => "e79883"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24339869"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            5 => array:3 [
              "identificador" => "bib0006"
              "etiqueta" => "6"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Elevated expression of &#946;1&#44;4-galactosyltransferase-I in cartilage and synovial tissue of patients with osteoarthritis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "W&#46; Liu"
                            1 => "Z&#46; Cui"
                            2 => "Y&#46; Wang"
                            3 => "X&#46; Zhu"
                            4 => "J&#46; Fan"
                            5 => "G&#46; Bao"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1007/s10753-011-9357-x"
                      "Revista" => array:7 [
                        "tituloSerie" => "Inflammation"
                        "fecha" => "2012"
                        "volumen" => "35"
                        "numero" => "2"
                        "paginaInicial" => "647"
                        "paginaFinal" => "655"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21750942"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            6 => array:3 [
              "identificador" => "bib0007"
              "etiqueta" => "7"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "&#946;1&#44;4-galactosyltransferase-I protects chondrocytes against TNF-induced apoptosis by blocking the TLR4 signaling pathway"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "H&#46; Wang"
                            1 => "Y&#46; Huang"
                            2 => "P&#46; Bao"
                            3 => "J&#46; Wu"
                            4 => "G&#46; Zeng"
                            5 => "X&#46; Hu"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:8 [
                        "tituloSerie" => "Am J Transl Res"
                        "fecha" => "2019"
                        "volumen" => "11"
                        "numero" => "7"
                        "paginaInicial" => "4358"
                        "paginaFinal" => "4366"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/31396341"
                            "web" => "Medline"
                          ]
                        ]
                        "itemHostRev" => array:3 [
                          "pii" => "S0140673610608884"
                          "estado" => "S300"
                          "issn" => "01406736"
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            7 => array:3 [
              "identificador" => "bib0008"
              "etiqueta" => "8"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "&#946;1&#44;4-galactosyltransferase-I in synovial tissue of collagen-induced rat model of rheumatoid arthritis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "H&#46; Wang"
                            1 => "D&#46; Xu"
                            2 => "R&#46; Tao"
                            3 => "X&#46; Ni"
                            4 => "A&#46; Shen"
                            5 => "Y&#46; Wang"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1007/s10238-010-0121-6"
                      "Revista" => array:7 [
                        "tituloSerie" => "Clin Exp Med"
                        "fecha" => "2011"
                        "volumen" => "11"
                        "numero" => "3"
                        "paginaInicial" => "147"
                        "paginaFinal" => "154"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21161318"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            8 => array:3 [
              "identificador" => "bib0009"
              "etiqueta" => "9"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Expression of &#946;-1&#44;4-galactosyltransferase I in a surgically-induced rat model of knee osteoarthritic synovitis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "Y&#46;H&#46; Wang"
                            1 => "X&#46;H&#46; Ni"
                            2 => "D&#46;W&#46; Xu"
                            3 => "H&#46; Cai"
                            4 => "H&#46;R&#46; Wang"
                            5 => "F&#46;R&#46; Sun"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:7 [
                        "tituloSerie" => "Chin Med J"
                        "fecha" => "2010"
                        "volumen" => "123"
                        "numero" => "21"
                        "paginaInicial" => "3067"
                        "paginaFinal" => "3073"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21162957"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            9 => array:3 [
              "identificador" => "bib0010"
              "etiqueta" => "10"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Transcriptional regulation of nuclear miRNAs in tumorigenesis &#40;Review&#41;"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "J&#46; Liu"
                            1 => "T&#46; Yang"
                            2 => "Z&#46; Huang"
                            3 => "H&#46; Chen"
                            4 => "Y&#46; Bai"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.3892/ijmm.2022.5148"
                      "Revista" => array:7 [
                        "tituloSerie" => "Int J Mol Med"
                        "fecha" => "2022"
                        "volumen" => "50"
                        "numero" => "1"
                        "paginaInicial" => "92"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/35593304"
                            "web" => "Medline"
                          ]
                        ]
                        "itemHostRev" => array:3 [
                          "pii" => "S1550728915010126"
                          "estado" => "S300"
                          "issn" => "15507289"
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            10 => array:3 [
              "identificador" => "bib0011"
              "etiqueta" => "11"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "miR-210-3p protects against osteoarthritis through inhibiting subchondral angiogenesis by targeting the expression of TGFBR1 and ID4"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "H&#46; Tang"
                            1 => "W&#46; Zhu"
                            2 => "L&#46; Cao"
                            3 => "J&#46; Zhang"
                            4 => "J&#46; Li"
                            5 => "D&#46; Ma"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:3 [
                        "tituloSerie" => "Front Immunol"
                        "fecha" => "2022"
                        "volumen" => "13"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            11 => array:3 [
              "identificador" => "bib0012"
              "etiqueta" => "12"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "MicroRNAs target on cartilage extracellular matrix degradation of knee osteoarthritis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "S&#46;H&#46; Li"
                            1 => "Q&#46;F&#46; Wu"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.26355/eurrev_202102_24821"
                      "Revista" => array:7 [
                        "tituloSerie" => "Eur Rev Med Pharmacol Sci"
                        "fecha" => "2021"
                        "volumen" => "25"
                        "numero" => "3"
                        "paginaInicial" => "1185"
                        "paginaFinal" => "1197"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/33629288"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            12 => array:3 [
              "identificador" => "bib0013"
              "etiqueta" => "13"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Melatonin Prevents Cartilage Degradation in Early-Stage Osteoarthritis Through Activation of miR-146a&#47;NRF2&#47;HO-1 Axis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "X&#46; Zhou"
                            1 => "Y&#46; Zhang"
                            2 => "M&#46; Hou"
                            3 => "H&#46; Liu"
                            4 => "H&#46; Yang"
                            5 => "X&#46; Chen"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/jbmr.4527"
                      "Revista" => array:7 [
                        "tituloSerie" => "J Bone Miner Res"
                        "fecha" => "2022"
                        "volumen" => "37"
                        "numero" => "5"
                        "paginaInicial" => "1056"
                        "paginaFinal" => "1072"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/35147250"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            13 => array:3 [
              "identificador" => "bib0014"
              "etiqueta" => "14"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Taraxasterol inhibits inflammation in osteoarthritis rat model by regulating miRNAs and NF-&#954;B signaling pathway"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "Z&#46; Xie"
                            1 => "B&#46; Wang"
                            2 => "C&#46; Zheng"
                            3 => "Y&#46; Qu"
                            4 => "J&#46; Xu"
                            5 => "B&#46; Wang"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.18388/abp.2020_6147"
                      "Revista" => array:8 [
                        "tituloSerie" => "Acta Biochim Pol"
                        "fecha" => "2022"
                        "volumen" => "69"
                        "numero" => "4"
                        "paginaInicial" => "811"
                        "paginaFinal" => "818"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/36440749"
                            "web" => "Medline"
                          ]
                        ]
                        "itemHostRev" => array:3 [
                          "pii" => "S0140673621023941"
                          "estado" => "S300"
                          "issn" => "01406736"
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            14 => array:3 [
              "identificador" => "bib0015"
              "etiqueta" => "15"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The synergistic function of miR-140-5p and miR-146a on TLR4-mediated cytokine secretion in osteoarthritic chondrocytes"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "I&#46; Papathanasiou"
                            1 => "C&#46; Balis"
                            2 => "V&#46; Trachana"
                            3 => "E&#46; Mourmoura"
                            4 => "A&#46; Tsezou"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.bbrc.2019.11.168"
                      "Revista" => array:8 [
                        "tituloSerie" => "Biochem Biophys Res Commun"
                        "fecha" => "2020"
                        "volumen" => "522"
                        "numero" => "3"
                        "paginaInicial" => "783"
                        "paginaFinal" => "791"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/31791577"
                            "web" => "Medline"
                          ]
                        ]
                        "itemHostRev" => array:3 [
                          "pii" => "S001651072034880X"
                          "estado" => "S300"
                          "issn" => "00165107"
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            15 => array:3 [
              "identificador" => "bib0016"
              "etiqueta" => "16"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The surgical destabilization of the medial meniscus &#40;DMM&#41; model of osteoarthritis in the 129&#47;SvEv mouse"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "S&#46;S&#46; Glasson"
                            1 => "T&#46;J&#46; Blanchet"
                            2 => "E&#46;A&#46; Morris"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:7 [
                        "tituloSerie" => "Osteoarthr Cartil"
                        "fecha" => "2007"
                        "volumen" => "15"
                        "numero" => "9"
                        "paginaInicial" => "1061"
                        "paginaFinal" => "1069"
                        "itemHostRev" => array:3 [
                          "pii" => "S0016508517301385"
                          "estado" => "S300"
                          "issn" => "00165085"
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            16 => array:3 [
              "identificador" => "bib0017"
              "etiqueta" => "17"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Animal research&#58; reporting <span class="elsevierStyleItalic">in vivo</span> experiments&#58; the ARRIVE guidelines"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "C&#46; Kilkenny"
                            1 => "W&#46; Browne"
                            2 => "I&#46;C&#46; Cuthill"
                            3 => "M&#46; Emerson"
                            4 => "D&#46;G&#46; Altman"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/j.1476-5381.2010.00872.x"
                      "Revista" => array:7 [
                        "tituloSerie" => "Br J Pharmacol"
                        "fecha" => "2010"
                        "volumen" => "160"
                        "numero" => "7"
                        "paginaInicial" => "1577"
                        "paginaFinal" => "1579"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20649561"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            17 => array:3 [
              "identificador" => "bib0018"
              "etiqueta" => "18"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Analysis of relative gene expression data using real-time quantitative PCR and the 2&#40;-Delta Delta C&#40;T&#41;&#41; Method"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "K&#46;J&#46; Livak"
                            1 => "T&#46;D&#46; Schmittgen"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1006/meth.2001.1262"
                      "Revista" => array:7 [
                        "tituloSerie" => "Methods"
                        "fecha" => "2001"
                        "volumen" => "25"
                        "numero" => "4"
                        "paginaInicial" => "402"
                        "paginaFinal" => "408"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11846609"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            18 => array:3 [
              "identificador" => "bib0019"
              "etiqueta" => "19"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Prediction of microRNA targets"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "P&#46; Mazi&#232;re"
                            1 => "A&#46;J&#46; Enright"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.drudis.2007.04.002"
                      "Revista" => array:7 [
                        "tituloSerie" => "Drug Discov Today"
                        "fecha" => "2007"
                        "volumen" => "12"
                        "numero" => "11-12"
                        "paginaInicial" => "452"
                        "paginaFinal" => "458"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17532529"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            19 => array:3 [
              "identificador" => "bib0020"
              "etiqueta" => "20"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The role of changes in extracellular matrix of cartilage in the presence of inflammation on the pathology of osteoarthritis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "M&#46; Maldonado"
                            1 => "J&#46; Nam"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:3 [
                        "tituloSerie" => "Biomed Res Int"
                        "fecha" => "2013"
                        "volumen" => "2013"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            20 => array:3 [
              "identificador" => "bib0021"
              "etiqueta" => "21"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Aging and osteoarthritis&#58; the role of chondrocyte senescence and aging changes in the cartilage matrix"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "R&#46;F&#46; Loeser"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Osteoarthr Cartil"
                        "fecha" => "2009"
                        "volumen" => "17"
                        "numero" => "8"
                        "paginaInicial" => "971"
                        "paginaFinal" => "979"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            21 => array:3 [
              "identificador" => "bib0022"
              "etiqueta" => "22"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Excessive sulfur oxidation in endoplasmic reticulum drives an inflammatory reaction of chondrocytes in aging mice"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "K&#46; Chen"
                            1 => "X&#46; Zhang"
                            2 => "Z&#46; Li"
                            3 => "X&#46; Yuan"
                            4 => "D&#46; Fu"
                            5 => "K&#46; Wu"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:3 [
                        "tituloSerie" => "Front Pharmacol"
                        "fecha" => "2022"
                        "volumen" => "13"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            22 => array:3 [
              "identificador" => "bib0023"
              "etiqueta" => "23"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "MiR-9-5p promotes M1 cell polarization in osteoarthritis progression by regulating NF-&#954;B and AMPK signaling pathways by targeting SIRT1"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "J&#46; Wang"
                            1 => "S&#46; Ma"
                            2 => "J&#46; Yu"
                            3 => "D&#46; Zuo"
                            4 => "X&#46; He"
                            5 => "H&#46; Peng"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Int Immunopharmacol"
                        "fecha" => "2021"
                        "volumen" => "101"
                        "numero" => "Pt A"
                        "itemHostRev" => array:3 [
                          "pii" => "S0016508518300040"
                          "estado" => "S300"
                          "issn" => "00165085"
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            23 => array:3 [
              "identificador" => "bib0024"
              "etiqueta" => "24"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "MiR-26a and miR-26b mediate osteoarthritis progression by targeting FUT4 via NF-&#954;B signaling pathway"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "J&#46; Hu"
                            1 => "Z&#46; Wang"
                            2 => "Y&#46; Pan"
                            3 => "J&#46; Ma"
                            4 => "X&#46; Miao"
                            5 => "X&#46; Qi"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.biocel.2017.12.003"
                      "Revista" => array:6 [
                        "tituloSerie" => "Int J Biochem Cell Biol"
                        "fecha" => "2018"
                        "volumen" => "94"
                        "paginaInicial" => "79"
                        "paginaFinal" => "88"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/29208566"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            24 => array:3 [
              "identificador" => "bib0025"
              "etiqueta" => "25"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "miR-146a-5p Promotes chondrocyte apoptosis and inhibits autophagy of osteoarthritis by targeting NUMB"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "H&#46; Zhang"
                            1 => "W&#46; Zheng"
                            2 => "D&#46; Li"
                            3 => "J&#46; Zheng"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1177/19476035211023550"
                      "Revista" => array:8 [
                        "tituloSerie" => "Cartilage"
                        "fecha" => "2021"
                        "volumen" => "13"
                        "numero" => "2"
                        "paginaInicial" => "1467s"
                        "paginaFinal" => "1477s"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/34315248"
                            "web" => "Medline"
                          ]
                        ]
                        "itemHostRev" => array:3 [
                          "pii" => "S2213858720303648"
                          "estado" => "S300"
                          "issn" => "22138587"
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            25 => array:3 [
              "identificador" => "bib0026"
              "etiqueta" => "26"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Hsa-miR-15a exerts protective effects against osteoarthritis by targeting aggrecanase-2 &#40;ADAMTS5&#41; in human chondrocytes"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "X&#46; Lu"
                            1 => "J&#46; Lin"
                            2 => "J&#46; Jin"
                            3 => "W&#46; Qian"
                            4 => "X&#46; Weng"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.3892/ijmm.2015.2446"
                      "Revista" => array:7 [
                        "tituloSerie" => "Int J Mol Med"
                        "fecha" => "2016"
                        "volumen" => "37"
                        "numero" => "2"
                        "paginaInicial" => "509"
                        "paginaFinal" => "516"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26707794"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            26 => array:3 [
              "identificador" => "bib0027"
              "etiqueta" => "27"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Deficiency of immune-responsive gene 1 exacerbates interleukin-1beta-elicited the inflammatory response of chondrocytes via enhancing the activation of NLRP3 inflammasome"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "L&#46; Cai"
                            1 => "J&#46; Huang"
                            2 => "D&#46; Huang"
                            3 => "H&#46; Lv"
                            4 => "D&#46; Wang"
                            5 => "H&#46; Wang"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:3 [
                        "tituloSerie" => "Int Immunopharmacol"
                        "fecha" => "2023"
                        "volumen" => "114"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            27 => array:3 [
              "identificador" => "bib0028"
              "etiqueta" => "28"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Daphnoretin relieves IL-1&#946;-mediated chondrocytes apoptosis via repressing endoplasmic reticulum stress and NLRP3 inflammasome"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "J&#46; Zhou"
                            1 => "Q&#46; Wang"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1186/s13018-022-03316-w"
                      "Revista" => array:7 [
                        "tituloSerie" => "J Orthop Surg Res"
                        "fecha" => "2022"
                        "volumen" => "17"
                        "numero" => "1"
                        "paginaInicial" => "487"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/36384642"
                            "web" => "Medline"
                          ]
                        ]
                        "itemHostRev" => array:3 [
                          "pii" => "S1550728921002331"
                          "estado" => "S300"
                          "issn" => "15507289"
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            28 => array:3 [
              "identificador" => "bib0029"
              "etiqueta" => "29"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "TNF&#47;TNFR&#8321; pathway and endoplasmic reticulum stress are involved in ofloxacin-induced apoptosis of juvenile canine chondrocytes"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "F&#46;T&#46; Zhang"
                            1 => "Y&#46; Ding"
                            2 => "Z&#46; Shah"
                            3 => "D&#46; Xing"
                            4 => "Y&#46; Gao"
                            5 => "D&#46;M&#46; Liu"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.taap.2014.02.003"
                      "Revista" => array:8 [
                        "tituloSerie" => "Toxicol Appl Pharmacol"
                        "fecha" => "2014"
                        "volumen" => "276"
                        "numero" => "2"
                        "paginaInicial" => "121"
                        "paginaFinal" => "128"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24582689"
                            "web" => "Medline"
                          ]
                        ]
                        "itemHostRev" => array:3 [
                          "pii" => "S2213858719301573"
                          "estado" => "S300"
                          "issn" => "22138587"
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            29 => array:3 [
              "identificador" => "bib0030"
              "etiqueta" => "30"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "CircFOXO3 protects against osteoarthritis by targeting its parental gene FOXO3 and activating PI3K&#47;AKT-mediated autophagy"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "C&#46; Zhao"
                            1 => "X&#46; Li"
                            2 => "G&#46; Sun"
                            3 => "P&#46; Liu"
                            4 => "K&#46; Kong"
                            5 => "X&#46; Chen"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1038/s41419-022-05390-8"
                      "Revista" => array:6 [
                        "tituloSerie" => "Cell Death Dis"
                        "fecha" => "2022"
                        "volumen" => "13"
                        "numero" => "11"
                        "paginaInicial" => "932"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/36344492"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            30 => array:3 [
              "identificador" => "bib0031"
              "etiqueta" => "31"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Aberrant regulation of autophagy linked to OA"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "J&#46; McHugh"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1038/s41584-022-00872-7"
                      "Revista" => array:6 [
                        "tituloSerie" => "Nat Rev Rheumatol"
                        "fecha" => "2022"
                        "volumen" => "18"
                        "numero" => "12"
                        "paginaInicial" => "672"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/36333453"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            31 => array:3 [
              "identificador" => "bib0032"
              "etiqueta" => "32"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Lactobacillus &#40;LA-1&#41; and butyrate inhibit osteoarthritis by controlling autophagy and inflammatory cell death of chondrocytes"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "K&#46;H&#46; Cho"
                            1 => "H&#46;S&#46; Na"
                            2 => "J&#46; Jhun"
                            3 => "J&#46;S&#46; Woo"
                            4 => "A&#46;R&#46; Lee"
                            5 => "S&#46;Y&#46; Lee"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:3 [
                        "tituloSerie" => "Front Immunol"
                        "fecha" => "2022"
                        "volumen" => "13"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            32 => array:3 [
              "identificador" => "bib0033"
              "etiqueta" => "33"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Semaphorin 3A-neuropilin-1 signaling modulates MMP13 expression in human osteoarthritic chondrocytes"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "S&#46; St&#246;ckl"
                            1 => "J&#46; Reichart"
                            2 => "M&#46; Zborilova"
                            3 => "B&#46; Johnstone"
                            4 => "S&#46; Gr&#228;ssel"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.3390/ijms232214180"
                      "Revista" => array:6 [
                        "tituloSerie" => "Int J Mol Sci"
                        "fecha" => "2022"
                        "volumen" => "23"
                        "numero" => "22"
                        "paginaInicial" => "14180"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/36430655"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            33 => array:3 [
              "identificador" => "bib0034"
              "etiqueta" => "34"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The role of autophagy in osteoarthritic cartilage"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "W&#46;C&#46; Kao"
                            1 => "J&#46;C&#46; Chen"
                            2 => "P&#46;C&#46; Liu"
                            3 => "C&#46;C&#46; Lu"
                            4 => "S&#46;Y&#46; Lin"
                            5 => "S&#46;C&#46; Chuang"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.3390/biom12101357"
                      "Revista" => array:7 [
                        "tituloSerie" => "Biomolecules"
                        "fecha" => "2022"
                        "volumen" => "12"
                        "numero" => "10"
                        "paginaInicial" => "1357"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/36291565"
                            "web" => "Medline"
                          ]
                        ]
                        "itemHostRev" => array:3 [
                          "pii" => "S014067362101919X"
                          "estado" => "S300"
                          "issn" => "01406736"
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            34 => array:3 [
              "identificador" => "bib0035"
              "etiqueta" => "35"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "HECTD1-mediated ubiquitination and degradation of Rubicon regulates autophagy and osteoarthritis pathogenesis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "S&#46; Liao"
                            1 => "Q&#46; Zheng"
                            2 => "H&#46; Shen"
                            3 => "Y&#46; Guang"
                            4 => "Y&#46; Xu"
                            5 => "X&#46; Zhang"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/art.42369"
                      "Revista" => array:7 [
                        "tituloSerie" => "Arthritis Rheumatol"
                        "fecha" => "2023"
                        "volumen" => "75"
                        "numero" => "3"
                        "paginaInicial" => "387"
                        "paginaFinal" => "400"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/36121967"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            35 => array:3 [
              "identificador" => "bib0036"
              "etiqueta" => "36"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "LncRNA ARFRP1 knockdown inhibits LPS-induced the injury of chondrocytes by regulation of NF-&#954;B pathway through modulating miR-15a-5p&#47;TLR4 axis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "G&#46; Zhang"
                            1 => "Q&#46; Zhang"
                            2 => "J&#46; Zhu"
                            3 => "J&#46; Tang"
                            4 => "M&#46; Nie"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:3 [
                        "tituloSerie" => "Life Sci"
                        "fecha" => "2020"
                        "volumen" => "261"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            36 => array:3 [
              "identificador" => "bib0037"
              "etiqueta" => "37"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Role of microRNA-15a-5p&#47;Sox9&#47;NF-&#954;B axis in inflammatory factors and apoptosis of murine nucleus pulposus cells in intervertebral disc degeneration"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "S&#46; Zhang"
                            1 => "S&#46; Song"
                            2 => "Y&#46; Zhuang"
                            3 => "J&#46; Hu"
                            4 => "W&#46; Cui"
                            5 => "X&#46; Wang"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:3 [
                        "tituloSerie" => "Life Sci"
                        "fecha" => "2021"
                        "volumen" => "277"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            37 => array:3 [
              "identificador" => "bib0038"
              "etiqueta" => "38"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "MicroRNA-15a-5p regulates the development of osteoarthritis by targeting PTHrP in chondrocytes"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "Z&#46;X&#46; Duan"
                            1 => "P&#46; Huang"
                            2 => "C&#46; Tu"
                            3 => "Q&#46; Liu"
                            4 => "S&#46;Q&#46; Li"
                            5 => "Z&#46;L&#46; Long"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:3 [
                        "tituloSerie" => "Biomed Res Int"
                        "fecha" => "2019"
                        "volumen" => "2019"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            38 => array:3 [
              "identificador" => "bib0039"
              "etiqueta" => "39"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "MiR-15a-5p regulates viability and matrix degradation of human osteoarthritis chondrocytes via targeting VEGFA"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "H&#46; Chen"
                            1 => "Y&#46; Tian"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.5582/bst.2016.01187"
                      "Revista" => array:7 [
                        "tituloSerie" => "Biosci Trends"
                        "fecha" => "2017"
                        "volumen" => "10"
                        "numero" => "6"
                        "paginaInicial" => "482"
                        "paginaFinal" => "488"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/27916780"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            39 => array:3 [
              "identificador" => "bib0040"
              "etiqueta" => "40"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "&#946;-1&#44;4-galactosyltransferase I promotes tumor necrosis factor-&#945; autocrine via the activation of MAP kinase signal pathways in Schwann cells"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "H&#46; Yang"
                            1 => "Q&#46; Yuan"
                            2 => "Q&#46; Chen"
                            3 => "C&#46; Li"
                            4 => "X&#46; Wu"
                            5 => "C&#46; Peng"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1007/s12031-011-9517-3"
                      "Revista" => array:7 [
                        "tituloSerie" => "J Mol Neurosci"
                        "fecha" => "2011"
                        "volumen" => "45"
                        "numero" => "2"
                        "paginaInicial" => "269"
                        "paginaFinal" => "276"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21461672"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            40 => array:3 [
              "identificador" => "bib0041"
              "etiqueta" => "41"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "CREBH&#58; a complex array of regulatory mechanisms in nutritional signaling&#44; metabolic inflammation&#44; and metabolic disease"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "H&#46; Wade"
                            1 => "K&#46; Pan"
                            2 => "Q&#46; Su"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:4 [
                        "tituloSerie" => "Mol Nutr Food Res"
                        "fecha" => "2021"
                        "volumen" => "65"
                        "numero" => "1"
                      ]
                    ]
                  ]
                ]
              ]
            ]
          ]
        ]
      ]
    ]
    "agradecimientos" => array:1 [
      0 => array:4 [
        "identificador" => "xack769798"
        "titulo" => "Acknowledgments"
        "texto" => "<p id="para0044" class="elsevierStylePara elsevierViewall">None&#46;</p>"
        "vista" => "all"
      ]
    ]
  ]
  "idiomaDefecto" => "en"
  "url" => "/18075932/000000780000000C/v4_202409020811/S180759322300090X/v4_202409020811/en/main.assets"
  "Apartado" => array:4 [
    "identificador" => "94924"
    "tipo" => "SECCION"
    "en" => array:2 [
      "titulo" => "Original articles"
      "idiomaDefecto" => true
    ]
    "idiomaDefecto" => "en"
  ]
  "PDF" => "https://static.elsevier.es/multimedia/18075932/000000780000000C/v4_202409020811/S180759322300090X/v4_202409020811/en/main.pdf?idApp=UINPBA00004N&text.app=https://www.elsevier.es/"
  "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S180759322300090X?idApp=UINPBA00004N"
]
Article information
ISSN: 18075932
Original language: English
The statistics are updated each day
Year/Month Html Pdf Total
2024 November 8 0 8
2024 October 68 22 90
2024 September 76 19 95
2024 August 67 15 82
2024 July 64 23 87
2024 June 39 16 55
2024 May 50 21 71
2024 April 60 23 83
2024 March 29 10 39
2024 February 14 17 31
2024 January 22 21 43
2023 December 28 31 59

Follow this link to access the full text of the article

es en pt

¿Es usted profesional sanitario apto para prescribir o dispensar medicamentos?

Are you a health professional able to prescribe or dispense drugs?

Você é um profissional de saúde habilitado a prescrever ou dispensar medicamentos