Información del artículo
Resumen
La esclerodermia es una enfermedad caracterizada por la acumulación excesiva de tejido fibroso que lleva a alteración en la estructura y función de la piel y de órganos internos. La principal citoquina involucrada en este proceso es el factor transformante de crecimiento beta y sus funciones se realizan principalmente a través de la señalización intracelular mediada por las proteínas Smad. Se han desarrollado estrategias para bloquear los efectos del factor transformante de crecimiento beta y la identificación de la vía de transmisión de señales proporciona nuevas herramientas para la investigación de futuras terapias, pero son necesarios más estudios en modelos animales y en humanos que logren reproducir en forma satisfactoria y segura los resultados.
El propósito de este artículo es analizar la función del factor transformante de crecimiento beta en la fisiopatología de la esclerodermia profundizando en la vía de señalización mediada por Smad; además, revisar los estudios que involucran estas proteínas como blanco terapéutico de moléculas y medicamentos como posibles tratamientos para la esclerodermia.
Palabras clave:
esclerodermia sistémica
TGF-beta
proteínas Smad
imatinib
Key words:
systemic scleroderma
TGF-beta
Smad proteins
imatinib
Summary
Scleroderma is a disease characterized by excessive accumulation of fibrous tissue that leads to alteration in the structure and function of the skin and internal organs. The main cytokine involved in this process is the transforming growth factor beta and their functions are carried out mainly through intracellular signaling mediated by Smad proteins. Several strategies have been developed to block the effects of the transforming growth factor beta and understanding the signaling pathway provides new tools for the investigation of future therapies, but more studies are needed in animal models and humans to get the replication of the results in a satisfactory and safe manner.
The purpose of this paper is to analyze the role of the transforming growth factor beta in the pathophysiology of scleroderma emphasizing the signaling pathway mediated by Smad; it is also to review some studies involving these proteins as therapeutic targets of molecules and drugs that could become potential treatments for scleroderma.
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Referencias
[1.]
S.A. Jimenez, C.T. Derk.
Following the molecular pathways toward an understanding of the pathogenesis of systemic sclerosis.
Ann Intern Med, 140 (2004), pp. 37-50
[2.]
T. Vuorio, V.M. Kahari, C. Black, E. Vuorio.
Expression of osteonectin, decorin, and transforming growth factor- beta 1 genes in fibroblasts cultured from patients with systemic sclerosis and morphea.
J Rheumatol, 18 (1991), pp. 247-251
[3.]
V.S. Rajkumar, K. Howell, K. Csiszar, C.P. Denton, C.M. Black, D.J. Abraham.
Shared expression of phenotypic markers in systemic sclerosis indicates a convergence of pericytes and fibroblasts to a myofibroblast lineage in fibrosis.
Arthritis Res Ther, 7 (2005), pp. R1113-R1123
[4.]
C. Chizzolini.
T cells, B cells, and polarized immune response in the pathogenesis of fibrosis and systemic sclerosis.
Curr Opin Rheumatol, 20 (2008), pp. 707-712
[5.]
M. Jinnin.
Mechanisms of skin fibrosis in systemic sclerosis.
J Dermatol, 37 (2010), pp. 11-25
[6.]
P. Helmbold, E. Fiedler, M. Fischer, W. Marsch.
Hyperplasia of dermal microvascular pericytes in scleroderma.
J Cutan Pathol, 31 (2004), pp. 431-440
[7.]
J. Peltonen, L. Kahari, S. Jaakkola, V.M. Kahari, J. Varga, J. Uitto, et al.
Evaluation of transforming growth factor beta and type I procollagen gene expression in fibrotic skin diseases by in situ hybridization.
J Invest Dermatol, 94 (1990), pp. 365-371
[8.]
J. Varga.
Scleroderma and Smads: dysfunctional Smad family dynamics culminating in fibrosis.
Arthritis Rheum, 46 (2002), pp. 1703-1713
[9.]
R. Derynck, Y. Zhang.
Intracellular signalling: the mad way to do it.
Curr Biol, 6 (1996), pp. 1226-1229
[10.]
Y. Mori, S.J. Chen, J. Varga.
Expression and regulation of intracellular SMAD signaling in scleroderma skin fibroblasts.
Arthritis Rheum, 48 (2003), pp. 1964-1978
[11.]
L. Zawel, J.L. Dai, P. Buckhaults, S. Zhou, K.W. Kinzler, B. Vogelstein, et al.
Human Smad3 and Smad4 are sequence-specific transcription activators.
Mol Cell, 1 (1998), pp. 611-617
[12.]
Y. Shi, J. Massague.
Mechanisms of TGF-beta signaling from cell membrane to the nucleus.
Cell, 113 (2003), pp. 685-700
[13.]
M. Lutz, P. Knaus.
Integration of the TGF-beta pathway into the cellular signalling network.
Cell Signal, 14 (2002), pp. 977-988
[14.]
K.C. Flanders.
Smad3 as a mediator of the fibrotic response.
Int J Exp Pathol, 85 (2004), pp. 47-64
[15.]
The Smads.
Genome Biol, 2 (2001),
[16.]
C.E. Runyan, H.W. Schnaper, A.C. Poncelet.
The role of internalization in transforming growth factor beta1- induced Smad2 association with Smad anchor for receptor activation (SARA) and Smad2-dependent signaling in human mesangial cells.
J Biol Chem, 280 (2005), pp. 8300-8308
[17.]
M. Kawabata, H. Inoue, A. Hanyu, T. Imamura, K. Miyazono.
Smad proteins exist as monomers in vivo and undergo homo- and hetero-oligomerization upon activation by serine/threonine kinase receptors.
EMBO J, 17 (1998), pp. 4056-4065
[18.]
Y. Inagaki, S. Truter, F. Ramirez.
Transforming growth factor-beta stimulates alpha 2(I) collagen gene expression through a cis-acting element that contains an Sp1-binding site.
J Biol Chem, 269 (1994), pp. 14828-14834
[19.]
S. Bhattacharyya, A.K. Ghosh, J. Pannu, Y. Mori, S. Takagawa, G. Chen, et al.
Fibroblast expression of the coactivator p300 governs the intensity of profibrotic response to transforming growth factor beta.
Arthritis Rheum, 52 (2005), pp. 1248-1258
[20.]
P. Greenwel, Y. Inagaki, W. Hu, M. Walsh, F. Ramirez.
Sp1 is required for the early response of alpha2(I) collagen to transforming growth factor-beta1.
J Biol Chem, 272 (1997), pp. 19738-19745
[21.]
H. Ihn, K. Yamane, Y. Asano, M. Jinnin, K. Tamaki.
Constitutively phosphorylated Smad3 interacts with Sp1 and p300 in scleroderma fibroblasts.
Rheumatology (Oxford), 45 (2006), pp. 157-165
[22.]
J. Massague, J. Seoane, D. Wotton.
Smad transcription factors.
Genes Dev, 19 (2005), pp. 2783-2810
[23.]
Y. Asano, H. Ihn, K. Yamane, M. Kubo, K. Tamaki.
Impaired Smad7-Smurf-mediated negative regulation of TGF-beta signaling in scleroderma fibroblasts.
J Clin Invest, 113 (2004), pp. 253-264
[24.]
A. Nakao, T. Imamura, S. Souchelnytskyi, M. Kawabata, A. Ishisaki, E. Oeda, et al.
TGF-beta receptormediated signalling through Smad2, Smad3 and Smad4.
EMBO J, 16 (1997), pp. 5353-5362
[25.]
S. Takagawa, G. Lakos, Y. Mori, T. Yamamoto, K. Nishioka, J. Varga.
Sustained activation of fibroblast transforming growth factor-beta/Smad signaling in a murine model of scleroderma.
J Invest Dermatol, 121 (2003), pp. 41-50
[26.]
P. Kavsak, R.K. Rasmussen, C.G. Causing, S. Bonni, H. Zhu, G.H. Thomsen, et al.
Smad7 binds to Smurf2 to form an E3 ubiquitin ligase that targets the TGF beta receptor for degradation.
Mol Cell, 6 (2000), pp. 1365-1375
[27.]
M. Afrakhte, A. Moren, S. Jossan, S. Itoh, K. Sampath, B. Westermark, et al.
Induction of inhibitory Smad6 and Smad7 mRNA by TGF-beta family members.
Biochem Biophys Res Commun, 249 (1998), pp. 505-511
[28.]
R.P. Nagarajan, F. Chen, W. Li, E. Vig, M.A. Harrington, H. Nakshatri, et al.
Repression of transforming-growthfactor- beta-mediated transcription by nuclear factor kappaB.
Biochem J, 348 Pt 3 (2000), pp. 591-596
[29.]
S. Ross, C.S. Hill.
How the Smads regulate transcription.
Int J Biochem Cell Biol, 40 (2008), pp. 383-408
[30.]
S. Itoh, P. ten Dijke.
Negative regulation of TGF-beta receptor/Smad signal transduction.
Curr Opin Cell Biol, 19 (2007), pp. 176-184
[31.]
H.J. Zhu, A.W. Burgess.
Regulation of transforming growth factor-beta signaling.
Mol Cell Biol Res Commun, 4 (2001), pp. 321-330
[32.]
Y. Tajima, K. Goto, M. Yoshida, K. Shinomiya, T. Sekimoto, Y. Yoneda, et al.
Chromosomal region maintenance 1 (CRM1)-dependent nuclear export of Smad ubiquitin regulatory factor 1 (Smurf1) is essential for negative regulation of transforming growth factor-beta signaling by Smad7.
J Biol Chem, 278 (2003), pp. 10716-10721
[33.]
L. Levy, M. Howell, D. Das, S. Harkin, V. Episkopou, C.S. Hill.
Arkadia activates Smad3/Smad4-dependent transcription by triggering signal-induced SnoN degradation.
Mol Cell Biol, 27 (2007), pp. 6068-6083
[34.]
A. Moustakas, C.H. Heldin.
Non-Smad TGF-beta signals.
J Cell Sci, 118 (2005), pp. 3573-3584
[35.]
M.C. Wilkes, E.B. Leof.
Transforming growth factor beta activation of c-Abl is independent of receptor internalization and regulated by phosphatidylinositol 3-kinase and PAK2 in mesenchymal cultures.
J Biol Chem, 281 (2006), pp. 27846-27854
[36.]
J. Varga, D. Abraham.
Systemic sclerosis: a prototypic multisystem fibrotic disorder.
J Clin Invest, 117 (2007), pp. 557-567
[37.]
T. Takahashi, H. Abe, H. Arai, T. Matsubara, K. Nagai, M. Matsuura, et al.
Activation of STAT3/Smad1 is a key signaling pathway for progression to glomerulosclerosis in experimental glomerulonephritis.
J Biol Chem, 280 (2005), pp. 7100-7106
[38.]
J. Pannu, Y. Asano, S. Nakerakanti, E. Smith, S. Jablonska, M. Blaszczyk, et al.
Smad1 pathway is activated in systemic sclerosis fibroblasts and is targeted by imatinib mesylate.
Arthritis Rheum, 58 (2008), pp. 2528-2537
[39.]
C. Dong, S. Zhu, T. Wang, W. Yoon, Z. Li, R.J. Alvarez, et al.
Deficient Smad7 expression: a putative molecular defect in scleroderma.
Proc Natl Acad Sci U S A, 99 (2002), pp. 3908-3913
[40.]
P.J. Christner, S.A. Jimenez.
Animal models of systemic sclerosis: insights into systemic sclerosis pathogenesis and potential therapeutic approaches.
Curr Opin Rheumatol, 16 (2004), pp. 746-752
[41.]
J.F. Callahan, J.L. Burgess, J.A. Fornwald, L.M. Gaster, J.D. Harling, F.P. Harrington, et al.
Identification of novel inhibitors of the transforming growth factor beta1 (TGF-beta1) type 1 receptor (ALK5).
J Med Chem, 45 (2002), pp. 999-1001
[42.]
M. Kondo, E. Cubillo, K. Tobiume, T. Shirakihara, N. Fukuda, H. Suzuki, et al.
A role for Id in the regulation of TGF-beta-induced epithelial-mesenchymal transdifferentiation.
Cell Death Differ, 11 (2004), pp. 1092-1101
[43.]
G.J. Prud’homme, C.A. Piccirillo.
The inhibitory effects of transforming growth factor-beta-1 (TGF-beta1) in autoimmune diseases.
J Autoimmun, 14 (2000), pp. 23-42
[44.]
Z. Mallat, A. Gojova, C. Marchiol-Fournigault, B. Esposito, C. Kamate, R. Merval, et al.
Inhibition of transforming growth factor-beta signaling accelerates atherosclerosis and induces an unstable plaque phenotype in mice.
Circ Res, 89 (2001), pp. 930-934
[45.]
L. Yu, W.A. Border, I. Anderson, M. McCourt, Y. Huang, N.A. Noble.
Combining TGF-beta inhibition and angiotensin II blockade results in enhanced antifibrotic effect.
Kidney Int, 66 (2004), pp. 1774-1784
[46.]
C.P. Denton, P.A. Merkel, D.E. Furst, D. Khanna, P. Emery, V.M. Hsu, et al.
Recombinant human anti-transforming growth factor beta1 antibody therapy in systemic sclerosis: a multicenter, randomized, placebocontrolled phase I/II trial of CAT-192.
Arthritis Rheum, 56 (2007), pp. 323-333
[47.]
W. Ishida, Y. Mori, G. Lakos, L. Sun, F. Shan, S. Bowes, et al.
Intracellular TGF-beta receptor blockade abrogates Smad-dependent fibroblast activation in vitro and in vivo.
J Invest Dermatol, 126 (2006), pp. 1733-1744
[48.]
J. Baraut, D. Farge, F. Jean-Louis, H. Kesmandt, C. Durant, F. Verrecchia, et al.
Cytokines in systemic sclerosis.
Pathol Biol, (2010),
[49.]
A. Nakao, M. Fujii, R. Matsumura, K. Kumano, Y. Saito, K. Miyazono, et al.
Transient gene transfer and expression of Smad7 prevents bleomycin-induced lung fibrosis in mice.
J Clin Invest, 104 (1999), pp. 5-11
[50.]
Y. Terada, S. Hanada, A. Nakao, M. Kuwahara, S. Sasaki, F. Marumo.
Gene transfer of Smad7 using electroporation of adenovirus prevents renal fibrosis in post-obstructed kidney.
Kidney Int, 61 (2002), pp. S94-S98
[51.]
J. Nie, X. Dou, W. Hao, X. Wang, W. Peng, Z. Jia, et al.
Smad7 gene transfer inhibits peritoneal fibrosis.
Kidney Int, 72 (2007), pp. 1336-1344
[52.]
H.Y. Lan.
Smad7 as a therapeutic agent for chronic kidney diseases.
Front Biosci, 13 (2008), pp. 4984-4992
[53.]
A. Nagler, H.Q. Miao, H. Aingorn, M. Pines, O. Genina, I. Vlodavsky.
Inhibition of collagen synthesis, smooth muscle cell proliferation, and injury-induced intimal hyperplasia by halofuginone.
Arterioscler Thromb Vasc Biol, 17 (1997), pp. 194-202
[54.]
O. Halevy, A. Nagler, F. Levi-Schaffer, O. Genina, M. Pines.
Inhibition of collagen type I synthesis by skin fibroblasts of graft versus host disease and scleroderma patients: effect of halofuginone.
Biochem Pharmacol, 52 (1996), pp. 1057-1063
[55.]
T.L. McGaha, R.G. Phelps, H. Spiera, C. Bona.
Halofuginone, an inhibitor of type-I collagen synthesis and skin sclerosis, blocks transforming-growth-factorbeta- mediated Smad3 activation in fibroblasts.
J Invest Dermatol, 118 (2002), pp. 461-470
[56.]
M. Pines, D. Snyder, S. Yarkoni, A. Nagler.
Halofuginone to treat fibrosis in chronic graft-versus-host disease and scleroderma.
Biol Blood Marrow Transplant, 9 (2003), pp. 417-425
[57.]
A. Nagler, N. Firman, R. Feferman, S. Cotev, M. Pines, S. Shoshan.
Reduction in pulmonary fibrosis in vivo by halofuginone.
Am J Respir Crit Care Med, 154 (1996), pp. 1082-1086
[58.]
M.H. Heeg, M.J. Koziolek, R. Vasko, L. Schaefer, K. Sharma, G.A. Muller, et al.
The antifibrotic effects of relaxin in human renal fibroblasts are mediated in part by inhibition of the Smad2 pathway.
Kidney Int, 68 (2005), pp. 96-109
[59.]
J.R. Seibold, J.H. Korn, R. Simms, P.J. Clements, L.W. Moreland, M.D. Mayes, et al.
Recombinant human relaxin in the treatment of scleroderma. A randomized, doubleblind, placebo-controlled trial.
Ann Intern Med, 132 (2000), pp. 871-879
[60.]
D. Khanna, P.J. Clements, D.E. Furst, J.H. Korn, M. Ellman, N. Rothfield, et al.
Recombinant human relaxin in the treatment of systemic sclerosis with diffuse cutaneous involvement: a randomized, double-blind, placebo-controlled trial.
Arthritis Rheum, 60 (2009), pp. 1102-1111
[61.]
M. Jinnin, H. Ihn, K. Tamaki.
Characterization of SIS3, a novel specific inhibitor of Smad3, and its effect on transforming growth factor-beta1-induced extracellular matrix expression.
Mol Pharmacol, 69 (2006), pp. 597-607
[62.]
X. Liu, S. Zhu, T. Wang, L. Hummers, F.M. Wigley, P.J. Goldschmidt-Clermont, et al.
Paclitaxel modulates TGFbeta signaling in scleroderma skin grafts in immunodeficient mice.
PLoS Med, 2 (2005), pp. e354
[63.]
D. Zhang, L. Sun, W. Xian, F. Liu, G. Ling, L. Xiao, et al.
Low-dose paclitaxel ameliorates renal fibrosis in rat UUO model by inhibition of TGF-beta/Smad activity.
Lab Invest, 90 (2010), pp. 436-447
[64.]
C.E. Daniels, M.C. Wilkes, M. Edens, T.J. Kottom, S.J. Murphy, A.H. Limper, et al.
Imatinib mesylate inhibits the profibrogenic activity of TGF-beta and prevents bleomycin-mediated lung fibrosis.
J Clin Invest, 114 (2004), pp. 1308-1316
[65.]
J.H. Distler, A. Jungel, L.C. Huber, U. Schulze-Horsel, J. Zwerina, R.E. Gay, et al.
Imatinib mesylate reduces production of extracellular matrix and prevents development of experimental dermal fibrosis.
Arthritis Rheum, 56 (2007), pp. 311-322
[66.]
P.L. van Daele, W.A. Dik, H.B. Thio, P.T. van Hal, J.A. van Laar, H. Hooijkaas, et al.
Is imatinib mesylate a promising drug in systemic sclerosis?.
Arthritis Rheum, 58 (2008), pp. 2549-2552
[67.]
J.H. Distler, B. Manger, B.M. Spriewald, G. Schett, O. Distler.
Treatment of pulmonary fibrosis for twenty weeks with imatinib mesylate in a patient with mixed connective tissue disease.
Arthritis Rheum, 58 (2008), pp. 2538-2542
[68.]
L. Chung, D.F. Fiorentino, M.J. Benbarak, A.S. Adler, M.M. Mariano, R.T. Paniagua, et al.
Molecular framework for response to imatinib mesylate in systemic sclerosis.
Arthritis Rheum, 60 (2009), pp. 584-591
[69.]
V.H. Ong, C.P. Denton.
Innovative therapies for systemic sclerosis.
Curr Opin Rheumatol, 22 (2010), pp. 264-272
[70.]
A. Taieb, J. Constans, F.X. Mahon.
A new therapeutic avenue for severe systemic sclerosis: imatinib mesylate.
Rev Med Interne, 29 (2008), pp. 173-175
[71.]
R.F. Spiera, J.K. Gordon, J.N. Mersten, C.M. Magro, M. Mehta, H.F. Wildman, et al.
Imatinib mesylate (Gleevec) in the treatment of diffuse cutaneous systemic sclerosis: results of a 1-year, phase IIa, single-arm, open-label clinical trial.
Ann Rheum Dis England, (2011), pp. 1003-1009
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