DIETAS BAJAS EN CALCIO EN EL HOMBRE Y EN ANIMALES DE EXPERIMENTACIÓN; MODELOS CLÁSICOS PARA ENTENDER LA HOMEÓSTASIS CÁLCICA Y EL SISTEMA ENDOCRINOLÓGICO DE LA VITAMINA D
Low calcium diets in humans and in experimental animals: classic models to understand calcium homeostasis and vitamin D endocrine system
N. Tolosa de Talamoni, V. Centeno
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EXPRESSION STUDY AND GENE REGULATION" ] ] "contieneTextoCompleto" => array:1 [ "es" => true ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "J CAMPIÓN, B MAESTRO, C CALLE, N DÁVILA, B BARCELÓ" "autores" => array:5 [ 0 => array:2 [ "Iniciales" => "J" "apellidos" => "CAMPIÓN" ] 1 => array:2 [ "Iniciales" => "B" "apellidos" => "MAESTRO" ] 2 => array:2 [ "Iniciales" => "C" "apellidos" => "CALLE" ] 3 => array:2 [ "Iniciales" => "N" "apellidos" => "DÁVILA" ] 4 => array:2 [ "Iniciales" => "B" "apellidos" => "BARCELÓ" ] ] ] ] ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/8612?idApp=UINPBA00004N" "url" => "/15750922/0000004600000007/v0_201307121157/8612/v0_201307121158/es/main.assets" ] "en" => array:12 [ "idiomaDefecto" => true "titulo" => "DIETAS BAJAS EN CALCIO EN EL HOMBRE Y EN ANIMALES DE EXPERIMENTACIÓN; MODELOS CLÁSICOS PARA ENTENDER LA HOMEÓSTASIS CÁLCICA Y EL SISTEMA ENDOCRINOLÓGICO DE LA VITAMINA D" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:1 [ "paginaInicial" => "241" ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "N Tolosa de Talamoni, V Centeno" "autores" => array:2 [ 0 => array:2 [ "Iniciales" => "N" "apellidos" => "Tolosa de Talamoni" ] 1 => array:2 [ "Iniciales" => "V" "apellidos" => "Centeno" ] ] ] ] "titulosAlternativos" => array:1 [ "en" => array:1 [ "titulo" => "Low calcium diets in humans and in experimental animals: classic models to understand calcium homeostasis and vitamin D endocrine system" ] ] "textoCompleto" => "<p class="elsevierStylePara"> The main role of the vitamin D related hormone is the regulation of intestinal Ca<span class="elsevierStyleSup">2+</span> absorption and Ca<span class="elsevierStyleSup">2+</span> homeostasis<span class="elsevierStyleSup">1</span>. Being the diet the only source of Ca<span class="elsevierStyleSup">2+</span>, adaptive mechanisms have evolved to control the amount of dietary calcium that is absorbed. When humans or experimental animals have low Ca intakes, the efficiency of intestinal Ca absorption increases<span class="elsevierStyleSup">2,3</span>. This mechanism of adaptation depends on the vitamin D status, mainly of the rate of synthesis of 1,25 (OH)<span class="elsevierStyleInf">2</span>D<span class="elsevierStyleInf">3</span><span class="elsevierStyleSup">4-6</span>. Increment of calbindin D<span class="elsevierStyleInf">9k</span> in mammals and calbindin D<span class="elsevierStyleInf">28k</span> in birds (cytosolic proteins presumably involved in the transcellular movement of Ca<span class="elsevierStyleSup">2+</span>) as well as higher levels of their respective mRNA are induced by dietary Ca<span class="elsevierStyleSup">2+</span> deficien- <br></br> cy<span class="elsevierStyleSup">7-9</span>. Low Ca diets not only affect vitamin D metabolism, but also parathyroid hormone (PTH) metabolism and parathyroid cells<span class="elsevierStyleSup">10</span>. In addition, molecular and biophysical changes occur in the plasma membrane of intestinal epithelial cells which may be involved in the global process of intestinal Ca absorption increment<span class="elsevierStyleSup">11,12</span>. Recent studies indicate that intestinal Ca absorption is also influenced by interactions between vitamin D receptor (VDR) genotype and environmental factors such as dietary calcium and vitamin D<span class="elsevierStyleSup">13</span>. A more detailed analysis of these issues will be explained in the following sections. </p><p class="elsevierStylePara"><span class="elsevierStyleBold">EFFECT OF DIETARY CALCIUM RESTRICTION ON VITAMIN D METABOLISM</span></p><p class="elsevierStylePara"> Cholecalciferol undergoes metabolic conversion before it exerts its biological effects. It is hydroxylated in two steps: the first hydroxylation occurs at the level of C-25 in the liver, and the second hydroxylation, which is produced in the kidney, is on the C-1 leading to the production of 1,25 (OH)<span class="elsevierStyleInf">2</span>D<span class="elsevierStyleInf">3</span> (calcitriol), the hormone derived from vitamin D. Another hydroxylation takes place in kidney and in other tissues under certain physiological conditions, producing the metabolite 24,25(OH)<span class="elsevierStyleInf">2</span>D<span class="elsevierStyleInf">3</span>. More than 40 metabolites are synthesized from vitamin D, but, 1,25(OH)<span class="elsevierStyleInf">2</span>D<span class="elsevierStyleInf">3</span> is the molecule responsible for the main actions of vitamin D<span class="elsevierStyleSup">14</span>. </p><p class="elsevierStylePara"> Feeding a low Ca diet results in significant stimulation of 1.25-dihydroxyvitamin D<span class="elsevierStyleInf">3</span> production in young rats, but not in aged rats<span class="elsevierStyleSup">15</span>. During the early stages of calcium deficiency, serum levels of PTH and 1,25 (OH)<span class="elsevierStyleInf">2</span>D<span class="elsevierStyleInf">3</span> increase in parallel and, after 3 weeks of Ca depletion, levels of calcitriol decline somewhat, but remain fourfold higher than those measured initially for about 6 weeks<span class="elsevierStyleSup">10</span>. The increase in serum levels of 1,25 (OH)<span class="elsevierStyleInf">2</span>D<span class="elsevierStyleInf">3</span> by a low Ca diet has been demonstrated in humans<span class="elsevierStyleSup">16</span>, chicks<span class="elsevierStyleSup">3</span>, ewes<span class="elsevierStyleSup">17</span> and rats<span class="elsevierStyleSup">4</span>. Schedl et al<span class="elsevierStyleSup">18</span> did not find increased levels of calcitriol in hamsters fed a low Ca diet although the ileum calcium absorption was increased. </p><p class="elsevierStylePara"> It is well established that PTH, secreted in response to hypocalcemia, causes a stimulatory effect of 1,25 (OH)<span class="elsevierStyleInf">2</span>D<span class="elsevierStyleInf">3</span> synthesis<span class="elsevierStyleSup">19</span>. However, when animals are given a low Ca and high vitamin D diet, the ability of PTH to increase kidney 1-hydroxylase is blunted and the metabolic clearance of 1,25 (OH)<span class="elsevierStyleInf">2</span>D<span class="elsevierStyleInf">3</span> is enhanced<span class="elsevierStyleSup">20</span>. Bell<span class="elsevierStyleSup">21</span> suggests that the renal synthesis of 1,25 (OH)<span class="elsevierStyleInf">2</span>D<span class="elsevierStyleInf">3</span> is not only modulated by PTH but also by the calcium receptor that has been recently described in kidney. </p><p class="elsevierStylePara"> Mortensen et al<span class="elsevierStyleSup">22</span> have found that the toxicity of 1- * (OH) D<span class="elsevierStyleInf">3</span>, a synthetic analogue of 1,25 (OH)<span class="elsevierStyleInf">2</span>D<span class="elsevierStyleInf">3</span>, was reduced in rats fed a semi-synthetic low-Ca diet compared with rats fed standard diet. The authors speculate that the use of diets low in Ca could allow the administration of higher doses of vitamin D derivatives or analogues without causing hypercalcemia. </p><p class="elsevierStylePara"> The number of VDR is also influenced by dietary calcium restriction<span class="elsevierStyleSup">23</span>. In contrast to the exogenous administration of 1,25 (OH)<span class="elsevierStyleInf">2</span>D<span class="elsevierStyleInf">3</span>, when high plasma levels of 1,25 (OH)<span class="elsevierStyleInf">2 </span>D<span class="elsevierStyleInf">3</span> are achieved by endogenous production of 1,25 (OH)<span class="elsevierStyleInf">2</span>D<span class="elsevierStyleInf">3</span> in response to chronic restriction of dietary calcium, intestinal VDR is not up-regulated and renal VDR content is down-regulated which indicates that some factor other than 1,25 (OH)<span class="elsevierStyleInf">2</span>D<span class="elsevierStyleInf">3</span> plays a role in regulating VDR content of tissues<span class="elsevierStyleSup">24</span>. </p><p class="elsevierStylePara"> The effect of low Ca diet on other metabolites derived from vitamin D is unclear. Fox et al<span class="elsevierStyleSup">25</span> did not show increase in the 1,25 (OH)<span class="elsevierStyleInf">2</span>D<span class="elsevierStyleInf">3</span> catabolism of rats fed a low Ca diet, but the metabolic renal clearance of 1,25 (OH)<span class="elsevierStyleInf">2</span>D<span class="elsevierStyleInf">3</span> was accelerated by dietary calcium restriction. On the contrary, Goff et al<span class="elsevierStyleSup">26</span> detected that dietary Ca restriction increases intestinal 24-hydroxylase activity 6 to 20-fold above that of rats fed a Ca replete diet. </p><p class="elsevierStylePara"><span class="elsevierStyleBold">INFLUENCE OF DIETARY CALCIUM DEPRIVATION ON PARATHYROID CELLS AND PTH METABOLISM</span></p><p class="elsevierStylePara"> It is well documented that PTH secretion is regulated by calcium, being the secretion stimulated by low and inhibited by high calcium levels<span class="elsevierStyleSup">27</span>. A sigmoidal relationship between PTH secretion and serum calcium has been confirmed in humans and experimental animals<span class="elsevierStyleSup">28,29</span>. Brown<span class="elsevierStyleSup">30</span> defined the set-point of this relationship, which is the calcium concentration producing half of the maximal inhibition of secretion. This parameter is useful in the analysis of PTH from patients with secondary hyperparathyroidism due to renal failure and in other conditions. </p><p class="elsevierStylePara"> The sensitivity of parathyroid glands is remarkable; small changes in serum calcium produce large changes in PTH secretion<span class="elsevierStyleSup">31</span>. A parathyroid calcium sensor has been recently characterized and cloned<span class="elsevierStyleSup">32</span>. This protein would mediate the physiological responses of the parathyroid cell to calcium. A variety of mutations inactivating the Ca sensor gene have been demonstrated in patients with familial hypocalciuric hypercalcemia<span class="elsevierStyleSup">31</span>. </p><p class="elsevierStylePara"> Low Ca diets affect parathyroid cell proliferation, regulation of PTH gene expression and PTH secretion. Naveh-Many et al<span class="elsevierStyleSup">33</span> have found that a Ca restricted diet leads to increased levels of PTH mRNA and a 10-fold incremented in parathyroid cell proliferation. </p><p class="elsevierStylePara"> Sela-Brown et al<span class="elsevierStyleSup">34</span> pointed out that the interrelationship of the effect of calcium and 1,25 (OH)<span class="elsevierStyleInf">2</span>D<span class="elsevierStyleInf">3</span> on the PTH gene and parathyroid cells is paradoxical. For instance, a dietary calcium deficiency results in low serum calcium leading to a marked, increment in serum 1,25 (OH)<span class="elsevierStyleInf">2</span>D<span class="elsevierStyleInf">3</span>, which would be expected to decrease PTH gene transcription. This dietary hypocalcemia is instead associated with an increase in PTH mRNA and serum PTH levels<span class="elsevierStyleSup">31</span>. Preliminary data indicate that the effect of Ca<span class="elsevierStyleSup">2+</span> on PTH mRNA levels in vivo occurs with no detectable changes in PTH gene transcription rate<span class="elsevierStyleSup">35</span>. The results suggest that the effect of calcium in vivo involves post-transcriptional mechanisms. Studies in vitro show that the 3'-untranslaated region of the PTH mRNA binds cytosolic proteins which may be involved in the post-transcriptional increase in PTH gene expression induced by hypocalcemia. These parathyroid proteins added in vitro to labeled PTH transcripts affect the transcript half-life. Hypocalcemic parathyroid proteins kept the transcript intact for a much longer period than those from control animals indicating that parathyroid proteins from hypocalcemic rats protect the PTH mRNA from degradation<span class="elsevierStyleSup">31</span>. Recently, it has been shown that calreticulin, a protein that binds to the conserved sequence KXGFFKR of steroid hormone receptors altering transcription of steroid responsive genes, is highly increased in the nuclear fraction of parathyroid gland and not in other tissues from hypocalcemic rats<span class="elsevierStyleSup">34</span>. The data suggest that calreticulin may prevent the transcriptional effect of 1,25 (OH)<span class="elsevierStyleInf">2</span>D<span class="elsevierStyleInf">3</span> on the PTH promoter. The effect of calreticulin might explain the refractoriness of the secondary hyperparathyroidism of many chronic renal failure patients to calcitriol treatment. </p><p class="elsevierStylePara"><span class="elsevierStyleBold">EFFECT OF DIETARY CALCIUM DEFICIENCY ON COMPOSITION OF INTESTINAL PLASMA MEMBRANES AND CALCIUM TRANSPORT</span></p><p class="elsevierStylePara"> Lipid and protein composition of plasma membranes from enterocytes have been demonstrated to be altered by Ca<span class="elsevierStyleSup">2+</span> restriction in the diet. Krawitt et al<span class="elsevierStyleSup">36</span> found that Ca<span class="elsevierStyleSup">2+</span> transport, measured by an in vitro gut sac technique, was increased in duodenum, jejunum and terminal ileum of rats fed a calcium-deficient diet for 7 days. They also observed that alkaline phosphatase activity was increased in the duodenum. They suggested that if alkaline phosphatase plays a role in this adaptation, it would be limited to the duodenal segment and might involve a process independent of active transport. Recently, in our laboratory, we have demonstrated that a low Ca diet increases the activity of this enzyme either in mature or in undifferentiated intestinal absorptive cells from chick duodena. The Ca<span class="elsevierStyleSup">2+</span> uptake by enterocytes was also enhanced in both cell types<span class="elsevierStyleSup">37</span>. </p><p class="elsevierStylePara"> The reactivity and availability of sulfhydryl groups from proteins of intestinal brush border membranes in chicks adapted to a low Ca diet were analyzed. By the Ellman <br></br> reaction, a threefold increment in HS<span class="elsevierStyleSup">­</span> group content was noted. By using DACM (N-7-dimethylamino-4-methylcoumarin-3-yl-maleimide), a fluorescent probe for HS<span class="elsevierStyleSup">­</span> groups, an adduct was formed which developed fluorescence. Fluorescence intensity developed more rapidly when the brush border membranes were from the low calcium than when from the control group. The reactivity of the membrane from the low Ca group was greater in the presence of detergent, which presumably exposed buried sulfhydryl groups. Both the maximum fluorescence intensity and the pseudo-first-order rate constant of the DACM reaction with brush border membranes (BBM) were higher in the Ca restricted group than in the control one<span class="elsevierStyleSup">11</span>. Previous results had shown similar changes in BBM sulfhydryl groups when 1,25 (OH)<span class="elsevierStyleInf">2</span>D<span class="elsevierStyleInf">3</span> was given to vitamin D-deficient chicks<span class="elsevierStyleSup">38</span>. Although the functional significance of the increment in HS<span class="elsevierStyleSup">­</span> groups promoted by the low Ca diet remains unknown, it is reasonable to think that the sulfhydryl status of the BBM proteins could be involved in the vitamin D-dependent intestinal absorption of calcium. </p><p class="elsevierStylePara"> Low Ca diet in experimental animals also causes changes in the two main proteins involved in the Ca<span class="elsevierStyleSup">2+</span> extrusion at the intestinal basolateral membranes (BLM): plasma membrane Ca<span class="elsevierStyleSup">2+</span>-ATPase and Na<span class="elsevierStyleSup">+</span>/Ca<span class="elsevierStyleSup">2+</span> exchanger. Regarding to the former protein, it has been demonstrated by using a monoclonal antibody against the human erythrocyte Ca<span class="elsevierStyleSup">2+</span> pump that cross reacts with the chick intestinal Ca<span class="elsevierStyleSup">2+</span> pump epitope, that either low Ca or low P diet incrases the number of intestinal plasma membrane Ca<span class="elsevierStyleSup">2+</span> pump units as occurs after vitamin D administration to D-deficient chicks<span class="elsevierStyleSup">39</span>. This appeared physiologically reasonable because of the stimulating effect of vitamin D and low Ca or low P diets on the intestinal Ca<span class="elsevierStyleSup">2+</span> absorption. Later on, it was demonstrated that Ca<span class="elsevierStyleSup">2+</span> pump mRNA concentration is increased by 1,25(OH)<span class="elsevierStyleInf">2</span>D<span class="elsevierStyleInf">3</span> due to an enhancement of the transcription rate of the Ca<span class="elsevierStyleSup">2+</span> pump gene<span class="elsevierStyleSup">40,41</span>. Recent data from our laboratory show that the activity of the intestinal Na<span class="elsevierStyleSup">+</span>/Ca<span class="elsevierStyleSup">2+</span> exchanger is also enhanced by feeding chicks a low Ca diet for 10 days. The activity of this exchanger was modified in enterocytes from the apex but not in cells from the crypt of the intestinal villus<span class="elsevierStyleSup">42</span>. Besides, it has been shown that lipid composition and fluidity of intestinal BLM are also altered by dietary calcium deficiency. Minor changes in the fatty acid content of the BLM were produced by the low Ca diet, such as a decrease in palmitic acid content and increase in the 22:5n3 and 22:6n3 fatty acids. However, by measurements of <br></br> steady-state fluorescence anisotropy, it was demonstrated that the lipid fluidity of diphenylhexatriene-labeled intestinal BLM was highly increased by the Ca<span class="elsevierStyleSup">2+</span> restriction in comparison to that of the control group<span class="elsevierStyleSup">12</span>. Thus, it appears that the Ca<span class="elsevierStyleSup">2+</span> exit through the BLM from the enterocytes in the animals adapted to a low Ca diet is greater than that from the control group because of the increment in the activity of the Ca<span class="elsevierStyleSup">2+</span> pump and Na<span class="elsevierStyleSup">+</span>/Ca<span class="elsevierStyleSup">2+</span> exchanger and changes in lipid composition and fluidity of BLM which could affect the microdomains of ion transporters and, hence, increase their activities. </p><p class="elsevierStylePara"> I<span class="elsevierStyleBold">NTERRELATIONSHIP BETWEEN CALCIUM ABSORPTION, LOW CALCIUM INTAKE AND VITAMIN D RECEPTOR GENOTYPE</span></p><p class="elsevierStylePara"> Genetic polymorphisms have been identified in the human VDR gene. In the past 5 years, a great body of information appeared in relation to the genetic polymorphisms defined within the intron between exons 7 and 8 as well as within the 3'untranslated region of exon 9<span class="elsevierStyleSup">43</span>. These polymorphisms seem to be correlated with bone mineral density (BMD) in several human populations and it was hypothesized that the determination of VDR genotypes could be useful as a predictor of development of osteoporosis<span class="elsevierStyleSup">44</span>. For instance, by using the restriction enzyme Bsm I on a DNA fragment amplified by the polymerase chain reaction wich includes the polymorphic Bsm I site in intron 7 of the gene, it is possible to determine 3 different genotypes: BB, Bb and bb. Genotype BB represents homozygous absence of the Bsm I restriction site, bb the homozygous presence of that site and Bb the heterozygous genotype. It has been found that women with the bb genotype had the highest BMD<span class="elsevierStyleSup">45</span>. The genotypes could be ranked as BB < Bb < bb in relation to BMD. However, negative and positive studies make this issue very controversial at present. </p><p class="elsevierStylePara"> The relationship between VDR genotypes and physiological parameters appears to be dependent on environmental factors like calcium and vitamin D intake and gene-environment interactions. It has been found that the calcium absorption of the BBAA haplotype (defined by restriction endonucleases Bsm I and Apa I) was lower than that of the homozygous haplotype (bbaa). Krall et al<span class="elsevierStyleSup">46</span> demonstrated influence of years elapsed since menopause and Ca intake on VDR alleles and rates of bone loss. They observed that the low Ca intake in healthy postmenopausal women increased the adverse association of the BB genotype with rapid femoral neck bone loss. The failure of the BB genotype to maintain calcium balance during Ca deficiency may result from an altered 1,25 (OH)<span class="elsevierStyleInf">2</span>D<span class="elsevierStyleInf">3</span> receptor status and inability to produce the positive adaptation of increasing the intestinal Ca absorption. Ferrari et al<span class="elsevierStyleSup">47</span> studied the relationship between VDR gene polymorphism and BMD in females from prepuberty to menopause and prospectively investigated the interaction of VDR genotypes with dietary Ca and BMD during childhood. In bb girls the BMD gain appeared to be higher than among the other genotypes when dietary Ca intake was low. BMD was significantly associated with VDR gene polymorphisms only before puberty. By increasing dietary Ca intake, BMD accrual was increased in Bb and BB prepubertal girls whereas bb subjects had the highest spontaneous BMD accrual and were not affected by Ca supplements. In summary, most of the recent studies reveal a consistent role of VDR alleles on intestinal Ca absorption and interaction with Ca intake even though the underlying molecular mechanisms remain unknown. </p>" "tienePdf" => false "PalabrasClave" => array:2 [ "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec204438" "palabras" => array:4 [ 0 => "Dieta pobre en calcio" 1 => "Vitamina D" 2 => "PTH" 3 => "Receptor de vitamina D" ] ] ] "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec204439" "palabras" => array:5 [ 0 => ": Low Ca diet" 1 => "Vitamin D" 2 => "PTH" 3 => "Calcium absorption" 4 => "VDR" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "es" => array:1 [ "resumen" => "El objetivo de este artículo es revisar la contribución aportada por el uso de dietas bajas en calcio, en el hombre y en animales de experimentación, para esclarecer la homeóstasis del calcio y del papel de la vitamina D. Se hace un énfasis especial en el efecto de estas dietas pobres en calcio sobre el metabolismo de la vitamina D, la síntesis y la secreción paratiroidea, el número de células paratiroideas y las propiedades químicas y físicas de las membranas plasmáticas de las células intestinales. También se discuten los datos referentes a la interacción entre el genotipo del receptor de la vitamina D y de la ingesta de Ca sobre la absorción intestinal de este mineral." ] "en" => array:1 [ "resumen" => "The aim of this article is to review the contribution performed by the use of low Ca diets either in humans or experimental animals to the knowledge of Ca homeostasis and the role of vitamin D. Special emphasis will be focused on the effect of these mineral restricted diets on vitamin D metabolism, parathyroid hormone (PTH) synthesis and secretion, number of parathyroid cells and chemical and physical properties of the intestinal plasma membranes. A brief analysis of the data regarding to the interaction between the vitamin D receptor (VDR) genotype and Ca intakes on intestinal Ca absorption will be also discussed." ] ] "bibliografia" => array:2 [ "titulo" => "Bibliography" "seccion" => array:1 [ 0 => array:1 [ "bibliografiaReferencia" => array:47 [ 0 => array:3 [ "identificador" => "bib1" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Vitamin D." 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ISSN: 15750922Original language: English
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