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PubMed1999

AP-1 and vitamin D receptor (VDR) signaling pathways converge at the rat osteocalcin VDR element: requirement for the internal activating protein-1 site for vitamin D-mediated trans-activation.

Responsiveness of genes to steroid hormones is a complex process involving synergistic and/or antagonistic interactions between specific receptors and other nonreceptor transcription factors. Thus, DNA recognition elements for steroid hormone receptors are often located among binding sites for other trans-acting factors. The hormonal form of vitamin D, 1,25-dihydroxyvitamin D3, stimulates transcription of the tissue-specific osteocalcin (OC) gene in osteoblastic cells. The rat OC vitamin D response element contains an internal acitvating protein-1 (AP-1) site. Here, we report for the first time that this AP-1 site is critical for the transcriptional enhancement of rat osteocalcin gene expression mediated by vitamin D. Precise mutations were introduced either in the steroid half-elements or in the internal AP-1 sequences. One mutation within the internal AP-1 site retained vitamin D receptor/retinoid X receptor binding equivalent to that of the wild-type sequence, but resulted in complete loss of vitamin D inducibility of the OC promoter. These results suggest a functional interaction between the hormone receptor and nuclear oncoproteins at the rat OC vitamin D response element. This cooperation of activities may have important consequences in physiological regulation of osteocalcin transcription during osteoblast differentiation and bone tissue development in vivo.

Animals↗

PubMedDate not supplied

Lipopolysaccharide negatively modulates vitamin D action by down-regulating expression of vitamin D-induced VDR in human monocytic THP-1 cells.

Vitamin D3, an important seco-steroid hormone for the regulation of body calcium homeostasis, promotes immature myeloid precursor cells to differentiate into monocytes/macrophages. Vitamin D receptor (VDR) belongs to a nuclear receptor super-family that mediates the genomic actions of vitamin D3 and regulates gene expression by binding with vitamin D response elements in the promoter region of the cognate gene. Thus by regulating gene expression, VDR plays an important role in modulating cellular events such as differentiation, apoptosis, and growth. Here we report lipopolysaccharide (LPS), a bacterial toxin; decreases VDR protein levels and thus inhibits VDR functions in the human blood monocytic cell line, THP-1. The biologically active form of vitamin D3, 1alpha,25-dihydroxy vitamin D3 [1,25(OH)2D3], induced VDR in THP-1 cells after 24 h treatment, and LPS inhibited 1,25(OH)2D3-mediated VDR induction. However, LPS and 1,25(OH)2D3 both increased VDR mRNA levels in THP-1 cells 20 h after treatment, as observed by real time RT-PCR. Moreover, LPS plus 1,25(OH)2D3 action on VDR mRNA level was additive and synergistic. A time course experiment up to 60 h showed an increase in VDR mRNA that was not preceded with an increase in VDR protein levels. Although the proteasome pathway plays an important role in VDR degradation, the proteasome inhibitor lactacystin had no effect on the LPS-mediated down-regulation of 1,25(OH)2D3 induced VDR levels. Reduced VDR levels by LPS were accompanied by decreased 1,25(OH)2D3/VDR function determined by VDR responsive 24-hydroxylase (CYP24) gene expression. The above results suggest that LPS impairs 1,25(OH)2D3/VDR functions, which may negatively affect the ability of 1,25(OH)2D3 to induce myeloid differentiation into monocytes/macrophages.

Cell Line↗

PubMed2006

Functional role of VDR in the activation of p27Kip1 by the VDR/Sp1 complex.

Our previous study demonstrate that vitamin D3 induces the binding of vitamin D3 receptor (VDR) to Sp1 transcription factor and stimulates p27Kip1 expression via the Sp1 consensus sequences in the promoter. Both VDR and Sp1 are transcriptional activators, it is unclear which protein functions as the transcription component of the VDR/Sp1 complex. To address this issue, we constructed the AF-2 deletion mutant of VDR and tested the effect of vitamin D3 on p27Kip1 expression. In consistent with our previous results, we found that expression of wild-type VDR in SW620 colon cancer cells, which expressed very low level of endogenous VDR, increased vitamin D3-stimulated p27Kip1 promoter activity and protein expression. On the contrary, expression of AF-2 deletion mutant had little effect. DNA affinity precipitation assay (DAPA) showed that both wild-type and deletion mutant of VDR bound to the DNA probe corresponding to the Sp1 binding site in the p27Kip1 promoter in a vitamin D3-dependent manner indicating deletion of AF-2 domain does not affect the interaction between VDR and Sp1. Chromatin immunoprecipitation (CHIP) assay also confirmed that VDR and its AF-2 deletion mutant bound to p27Kip1 promoter in vivo. We found that deletion of AF-2 domain abolished the interaction of coactivators SRC-1 and DRIP205 with VDR. Taken together, our results suggest that VDR functions as the transactivation component of the VDR/Sp1 complex to trigger gene expression.

Cell Line, Tumor↗

PubMed2007

VDR-mediated inhibition of DKK1 and SFRP2 suppresses adipogenic differentiation of murine bone marrow stromal cells.

Osteoblasts and adipocytes are thought to derive from a common bone marrow stromal cell (BMSC) precursor. Activation of the canonical Wnt signaling pathway plays a pivotal role in the differentiation of BMSCs along either of these two lineages, promoting osteogenesis and inhibiting adipogenesis. Liganded nuclear receptors, including the vitamin D receptor (VDR) and peroxisomal proliferator-activated receptor gamma (PPARgamma), can also affect BMSCs differentiation. To address whether VDR ablation modulates the differentiation of BMSCs into the osteoblast or adipogenic lineages, BMSCs were isolated from VDR null mice and from their wild-type littermates. VDR ablation did not alter osteoblastic differentiation. However, when cultured under adipogenic conditions, BMSCs from the VDR null mice expressed higher mRNA levels of PPARgamma and of markers of adipogenic differentiation. An increase in the size and number of mature adipocyte foci was also observed in cultures isolated from VDR null mice relative to those isolated from wild-type mice. To address whether the increased adipogenesis observed in the VDR null cultures was associated with inhibition of the canonical Wnt signaling pathway, mRNA levels for DKK1 and SFRP2 were examined. Cultures from the VDR null mice expressed higher levels of mRNA encoding DKK1 and SFRP2 than did the wild-type cultures. This difference is, at least in part, due to ligand-dependent actions of the VDR, since 1,25-dihydroxyvitamin D3 suppressed DKK1 and SFRP2 expression in wild-type cultures. Thus, the VDR inhibits adipogenesis of BMSCs at least in part by suppressing the expression of inhibitors of the canonical Wnt signaling pathway.

Adipocytes↗

PubMed2004

Ligand modulates VDR-Ser/Thr protein phosphatase interaction and p70S6 kinase phosphorylation in a cell-context-dependent manner.

We have recently shown that in colon cancer cells, Vitamin D receptor (VDR) interacts with the catalytic subunit of Ser/Thr protein phosphatases, PP1c and PP2Ac, and induces their enzymatic activity in a ligand-dependent manner. The VDR-PP1c and VDR-PP2Ac interactions were ligand independent in vivo, and 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3))-mediated increase in VDR-associated phosphatase activity resulted in dephosphorylation and inactivation of p70S6 kinase in colon cancer cells. Here, we demonstrate that in myeloid leukemia cells, 1,25(OH)(2)D(3) treatment increased the Thr389 phosphorylation of p70S6 kinase. Accordingly, 1,25(OH)(2)D(3) decreased VDR-associated Ser/Thr protein phosphatase activity by dissociating VDR-PP1c and VDR-PP2Ac interactions. Further, 1,25(OH)(2)D(3) increased the association between VDR and Thr389 phosphorylated p70S6 kinase. Finally, by using non-secosteroidal VDR ligands, we demonstrate a separation between transactivation and p70S6 kinase phosphorylation activities of VDR and show pharmacologically that p70S6 kinase phosphorylation correlates with HL-60 cell differentiation.

Cell Line, Tumor↗

PubMed1999

Vitamin D3 receptor (VDR) expression in HC-11 mammary cells: regulation by growth-modulatory agents, differentiation, and Ha-ras transformation.

HC-11 mammary epithelial cells which originate from midpregnant BALB/c mice are able to differentiate in culture after epidermal (EGF) or basic fibroblast (FGF) growth factor pretreatment followed by lactogenic hormone stimulation (Dexamethasone, Insulin, and Prolactin - DIP). In our study, HC-11 cells exhibited specific vitamin D3 receptors (VDR) determined by Northern analysis or flow cytometry and responded to 10 nM vitamin D3 treatment displaying strong growth inhibition, arrest in G0/G1 phase without evidence of apoptosis, and VDR mRNA reduction, although the percentage of cells expressing VDR protein remained unchanged. In an attempt to verify if there was a correlation between the growth state of the cells and VDR levels, we have examined the effects of growth modulators such as EGF/bFGF and confluency and transformation by Ha-ras. A down-regulation of VDR expression was observed after Ha-ras transformation of HC-11 cells which desensitized the cells to the growth inhibitory effects of vitamin D3. EGF or bFGF decreased VDR in parental cells and EGF antagonized the antiproliferative activity of vitamin D3. As well, transition from proliferating to confluent state significantly reduced VDR levels only in parental cells. DIP-induced HC-11 cell differentiation (monitored by beta-casein transcripts), although leading to cell cycle arrest, increased VDR mRNA content, which seems to be rather related to lactogenic hormone induction than to differentiation itself. In fact, DIP-stimulated HC-11 cells in the absence of EGF pretreatment, or DIP-treated HC-11ras cultures, also displayed up-regulated VDR level even in the absence of differentiation. Concluding, mammary VDR levels might be regulated by growth modulating agents, by physiological conditions of the gland, and by the ras-mediated malignant transformation.

Animals↗

PubMed1999

Association of VDR and estrogen receptor genotypes with bone mass in postmenopausal Caucasian women: different conclusions with different analyses and the implications.

Much work has been done on the association between vitamin D receptor (VDR) genotypes and bone mineral density (BMD). Despite considerable effort, the results are inconsistent. While the VDR association remains unresolved, studies have expanded to other candidate genes (i.e., estrogen receptor (ER) genotypes), also yielding inconsistent results. A few studies have suggested that interaction effects between VDR and ER genotypes significantly affect BMD. We assessed associations of BMD with VDR BsmI genotypes, and ER XbaI and PvuII polymorphisms (denoted as ERX and ERP respectively) with spine, femoral neck, distal radius BMD, and with total body bone mineral content (tbBMC) in 108 US Mid-western postmenopausal Caucasian women. We statistically controlled for confounding factors such as height, weight, etc., in the analysis. No significant association was detected for ER genotypes with spine and radius BMD, or for VDR genotypes with femoral neck and radius BMD and tbBMC. No significant interaction between VDR and ER genotypes was detected in our sample. However, the VDR genotypes are significantly (p = 0.004) associated with approximately 5.8% spine BMD variation. Both ERX and ERP genotypes are significantly (p = 0.02) associated with approximately 3.5% femoral neck BMD variation. ERX genotypes are significantly (p = 0.03) associated with approximately 2.4% tbBMC variation. However, if the data were analyzed by simple ANOVA as in some previous studies, without adjusting statistically for confounding factors, all the significant results we found here would have gone undetected. Our findings suggest that: (1) VDR and ER genotypes may have different effects on BMD at different sites and on tbBMC; and (2) if significant factors influencing bone are not appropriately controlled, true significant associations can easily be missed. These findings may offer a partial explanation for some of the earlier inconsistent results of association studies on BMD with VDR and ER genotypes.

Absorptiometry, Photon↗

PubMed1999

Analysis of 1,25-dihydroxyvitamin D(3) receptors (VDR) in basal cell carcinomas.

We have analyzed expression of 1,25-dihydroxyvitamin D(3) receptor (VDR) protein and mRNA in basal cell carcinomas (BCC) of human skin. VDR immunoreactivity in BCCs was compared with the staining pattern of the proliferation marker Ki-67 in the same tumors. Additionally, VDR staining was compared to staining pattern of apoptotic cells by terminal UTP nucleotide end labeling assay. Frozen sections of superficial type, nodular type, and fibrosing type BCCs were consistently immunoreactive for VDR (mAb 9A7gamma) with almost every tumor cell labeled (n = 15). In general, VDR staining was pronounced in peripheral tumor cells. VDR immunoreactivity was consistently stronger in tumor cells than in adjacent or unaffected epidermis. No visual correlation was found in BCCs comparing labeling patterns of Ki-67-positive or apoptotic cells and mAb 9A7gamma. VDR mRNA was increased in BCCs (n = 6) compared to normal human skin (n = 5), as revealed by reverse transcription-polymerase chain reaction analysis. Our findings indicate that VDR is strongly expressed in BCCs and may be involved in the growth regulation of this tumour, and VDR mRNA and protein are increased in BCCs as compared to normal human epidermis.

Antibodies, Monoclonal↗

PubMed1998

Localization of 1,25-dihydroxyvitamin D3 receptor (VDR) expression in human prostate.

1,25-dihydroxyvitamin D3 (1,25(OH)2D3) has been found to have a variety of physiological functions, including effects on growth and differentiation in normal and malignant cells. The antiproliferative effects of 1,25(OH)2D3 are reported to be mediated through the genomic signaling pathway by binding to a specific high affinity receptor protein, the 1,25-dihydroxyvitamin D3 receptor (VDR). VDR has been localized in a variety of tissues, but little is known about VDR distribution in human prostate. In this study, we raised an antibody against a synthetic peptide corresponding to amino acids 10-24 of human vitamin D receptor. The sequence selected for immunization is identical in human, rat and mouse VDR. Based on this antibody, we developed an immunohistochemical method suitable for studying VDR expression in paraffin-embedded tissue. The immunohistochemical staining was verified using classical target organs for vitamin D (kidney, intestine, skin). With this method, we studied VDR localization on paraffin-embedded human prostatic tissue obtained from 8 patients undergoing radical prostatectomy for urinary bladder cancer and demonstrate VDR expression in the secretory epithelial and few stromal cells of human prostate. The nuclear staining in the secretory epithelial cells was concentrated near the nuclear membrane and in discrete foci in the nucleoplasm. This suggests that effects of 1,25-dihydroxyvitamin D3 are mediated through VDR in these cells. Moreover our result indicates that there are strong variations in VDR expression between prostatic samples.

Amino Acid Sequence↗

PubMed2006

Vitamin D receptor (VDR) localization in human promyelocytic leukemia cells.

Although vitamin D analogs are known to induce the differentiation of the HL-60 promyelocytic leukemia cells, the effect of vitamin D analogs on the distribution of vitamin D receptor (VDR) in these cells is not well studied. This report showed, by confocal microscopy, that VDR mainly resided in the cytoplasm in the absence of VDR ligands. When cells were treated with 19-nor-1alpha,25-(OH)(2)D(2) or 1,25(OH)(2)D(3), VDR moved from the cytoplasm into the nucleus in a time-dependent manner. VDR could be observed in the nucleus as early as 6 h after drug treatment and was still observed in the nucleus 3 days after one single addition of 100 nM 19-nor-1alpha,25-(OH)(2)D(2) or 1,25(OH)(2)D(3). The VDR protein level was significantly increased by 19-nor-1alpha,25-(OH)(2)D(2) or 1,25(OH)(2)D(3) in a dose-dependent manner, while the VDR mRNA level was not affected by either compound. These results suggest that binding of vitamin D analogs to VDR induced receptor translocation into the nucleus, which stabilizes the receptor, resulting in an accumulation of the VDR protein.

Cell Nucleus↗

PubMed2006

Overexpression of ER and VDR is not sufficient to make ER-negative MDA-MB231 breast cancer cells responsive to 1alpha-hydroxyvitamin D5.

1alpha-hydroxyvitamin D(5) [1alpha(OH)D(5)] is an active vitamin D analog showing promising chemopreventive effect in breast carcinogenesis. We previously reported that estrogen receptor (ER)-positive breast cancer cells were sensitive, whereas ER-negative breast cancer cells were relatively resistant to their antiproliferative effects. In the present study, we used ER-negative MDA-MB231, ER-transfected MDA-MB231 (S30) and ER-positive BT474 cell lines to evaluate the possible association between ER status and cellular sensitivity to 1alpha(OH)D(5) treatment. Our results demonstrate that ER expression in ER-negative breast cancer cells (S30) did not increase the sensitivity to 1alpha(OH)D(5), whereas in ER-positive BT474 cells, the significant antiproliferative effect of 1alpha(OH)D(5) was correlated with the downregulation of ER and progesterone receptor expression. Further analysis indicated that both MDA-MB231 and S30 cells express low vitamin D receptor (VDR) at transcriptional level and protein level. However, transfection of VDR failed to restore the sensitivity to 1alpha(OH)D(5) in MDA-MB231 and S30 cells, although VDR direct target gene CYP24 was more responsive to 1alpha(OH)D(5) treatment in MDA-MB231 and S30 cells overexpressing VDR. In addition, nuclear receptor cofactors NCoR1 and SRC1 that could potentially affect VDR action were also low in both MDA-MB231 and S30 cells in comparison with ER-positive, vitamin D-sensitive BT474 cells. These results suggest that in addition to the increased ER and VDR expression, the intact VDR signaling machinery as present in ER-positive, vitamin D-sensitive cells is essential for the antiproliferative action of vitamin D, whereas the direct VDR target genes such as CYP24 can remain responsive to augmented VDR expression.

Breast Neoplasms↗

PubMed2000

VDR-Alien: a novel, DNA-selective vitamin D(3) receptor-corepressor partnership.

The vitamin D receptor (VDR) is a transcription factor that transmits incoming 1,25-dihydroxyvitamin D(3) (1alpha,25(OH)(2)D(3)) signaling via combined contact with coactivator proteins and specific DNA binding sites (VDREs), which ultimately results in activation of transcription. In contrast, the mechanisms of transcriptional repression via the VDR are less well understood. This study documents VDR-dependent transcriptional repression largely via histone deacetylase (HDAC) activity. Direct, ligand-sensitive protein-protein interaction of the VDR with the nuclear receptor corepressor (NCoR) and a novel corepressor, called Alien, was demonstrated to be comparable but independent of the VDR AF-2 trans-activation domain. Functional assays indicated that Alien, but not NCoR, displays selectivity for different VDRE structures for transferring these repressive effects into gene regulatory activities. Moreover, superrepression via Alien was found to be affected only in part by HDAC inhibitors such as trichostatin A. Finally, for a dissociation of VDR-Alien complexes in vitro and in vivo, higher ligand concentrations were needed than for a dissociation of VDR-NCoR complexes. This suggests that Alien and NCoR are using different interfaces for interaction with the VDR and different pathways for mediating superrepression, which in turn characterizes Alien as a representative of a new class of corepressors. Taken together, association of the VDR with corepressor proteins provides a further level of transcriptional regulation, which is emerging as a complex network of protein-protein interaction-mediated control.

Animals↗

PubMed2004

Role of TAFII-17, a VDR binding protein, in the increased osteoclast formation in Paget's Disease.

UNLABELLED: In contrast to normal OCL precursors, pagetic OCL precursors express MVNP and form OCL at physiologic concentrations of 1,25(OH)2D3, as do normal OCL precursors transfected with the MVNP gene. Using a GST-VDR chimeric protein, we identified TAFII-17 as VDR binding protein expressed by pagetic OCL precursors and MVNP transduced normal OCL precursors. TAF(II)-17 was in part responsible for the increased 1,25(OH)2D3 responsivity of pagetic OCL precursors. INTRODUCTION: Pagetic osteoclasts (OCLs) and their precursors express measles virus nucleocapsid protein (MVNP) and form large numbers of OCLs at low concentrations of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3]. Similarly, normal OCL precursors transfected with MVNP also form OCLs at low concentrations of 1,25(OH)2D3. These results suggest that expression of MVNP in OCL precursors enhances vitamin D receptor (VDR)-mediated gene transcription. MATERIALS AND METHODS: To determine the mechanism for the increased OCL formation capacity of pagetic OCL precursors in response to 1,25(OH)2D3, lysates from pagetic and MVNP-transduced normal OCL precursors were incubated with a GST-VDR chimeric protein. RESULTS: A 17-kDa peptide that bound VDR was detected in MVNP-transduced cells and pagetic OCL precursors treated with 1,25(OH)2D3. This peptide was identified as TAFII-17, a component of the TFIID transcription complex. Expression of increased levels of TAFII-17 in cells allowed TAFII-17 to bind to VDR at low concentrations of 1,25(OH)2D3. An antisense oligonucelotide (AS-ODN) to TAFII-17 significantly decreased OCL formation in response to 1,25(OH)2D3 in pagetic but not normal marrow cultures by approximately 40%. Transfection of TAFII-17 or MVNP into NIH3T3 cells increased VDR transcriptional activity as measured by DR-3 reporter assays. CONCLUSION: These data show that expression of the MVNP gene in OCL precursors results in increased levels of TAFII-17. TAFII-17 can bind VDR at low concentrations of 1,25(OH)2D3. These results suggest that MVNP expression in Paget's OCL precursors increases expression of a component(s) of the VDR transcription complex that can increase OCL formation.

Bone Marrow Cells↗

PubMed2004

The influence of VDR genotype and exercise on ultrasound parameters in young adult Japanese women.

We investigated the relation between the vitamin D receptor (VDR) genotype and bone mass including the effect of exercise history as a measure of physical activity. BUA (broadband ultrasound attenuation), SOS (speed of sound) and Stiffness index of the calcaneus were measured using an ultrasound bone densitometer in 105 Japanese young adult women (age: mean+/-SD 20.4+/-4.1 years, ranged 18-37) by the calcaneal ultra sound measurement to assess bone mass. Physical activity was measured using a questionnaire about exercise and was calculated as exercise hours per week during prepuberty (elementary school), puberty (junior and senior high school) and a current period (from >18 years old). VDR genotype was determined by the BsmI restriction site of the VDR gene. Significant differences were observed in age-adjusted and menarche age-adjusted SOS and Stiffness between BsmI VDR genotypes. We also examined the interaction between VDR genotype and the amount of exercise. The association between ultrasound parameters and exercise hours per week was evaluated with simple regression analysis according to VDR genotype. There was a significant difference in the slope between VDR genotypes in regression analysis of exercise hours per week during senior high school for SOS (P<0.05). Furthermore, we conducted multiple regression analysis to examine the contribution of each factor to ultrasound parameters. VDR genotype was a significant independent variable for SOS (P<0.05). Exercise hours each week during senior high school was a significant independent variable for all ultrasound parameters (all: P<0.001). In conclusion, there was a partial significant relation between VDR genotype and ultrasound parameters, but the exercise hours each week during senior high school was the strongest independent factor for bone mass in young adult Japanese women.

Adolescent↗

PubMed2006

Cardiovascular disease in chronic kidney failure: the role of VDR activators.

Vitamin D3 is modified by vitamin D3 25-hydroxylase in the liver, and by 25-hydroxyvitamin D3 1alpha-hydroxylase (CYP27B1) in the kidney, to form the active metabolite 1alpha,25-dihydroxyvitamin D3. Several vitamin D receptor (VDR) activators, including paricalcitol and calcitriol, are currently available for the treatment of hyperparathyroidism secondary to chronic kidney disease (CKD). CKD patients encounter a much higher risk of cardiovascular disease than do members of the general public, and recent clinical observations have shown that VDR activator therapy provides survival benefit for CKD patients in the rank order of paricalcitol > calcitriol > no VDR activator therapy, independent of parathyroid hormone, phosphorus and calcium. One possible explanation for this observation is that VDR activators exert a positive impact on cardiovascular functions. Studies in animals with disrupted genes involved in the vitamin D signaling pathway have provided some interesting data. For example, in mice lacking VDR or CYP27B1, it was found that in addition to the expected phenotype (hypocalcemia, secondary hyperparathyroidism and osteomalacia), expression of renin or atrial natriuretic peptide was elevated. The mice also developed hypertension and cardiac hypertrophy. Gene expression profiling studies have revealed that VDR may play a role in regulating smooth-muscle-cell (SMC) proliferation, thrombosis, fibrinolysis and vessel relaxation. Paricalcitol and calcitriol are equally potent at suppressing plasminogen activator inhibitor-1 synthesis and inhibiting cellular proliferation in human coronary artery SMCs. The effect of VDR activators on the modulation of renin expression and vascular functions may be factors that contribute to reduced mortality and morbidity risk in VDR-activator-treated CKD patients. In this review, we discuss recent preclinical and clinical data regarding the role of VDR and its ligands in the cardiovascular system.

Calcitriol↗

PubMed2004

Dietary calcium, vitamin D, VDR genotypes and colorectal cancer.

The vitamin D receptor (VDR) may importantly modulate risk of colorectal cancer either independently or in conjunction with calcium and vitamin D intake. We evaluate the association between calcium, vitamin D, dairy products, and VDR polymorphisms in 2 case-control studies of colon and rectal cancer (n = 2,306 cases and 2,749 controls). Dietary intake was evaluated using a detailed diet history questionnaire. Two VDR polymorphisms were evaluated: an intron 8 Bsm 1 polymorphism and a 3' untranslated region poly-A length polymorphism (designated S for short and L for long). The SS genotype reduced risk of colorectal cancer for men (odds ratio [OR] = 0.71; 95% confidence interval [CI] = 0.55-0.92). High levels of calcium intake reduced risk of rectal cancer in women (OR = 0.39; 95% CI = 0.24-0.64) but were not associated with rectal cancer in men (OR = 1.02; 95% CI = 0.66-1.56). Similar reduced rectal cancer risk among women was observed at high levels of vitamin D (OR = 0.52; 95% CI = 0.32-0.85) and low-fat dairy products (OR = 0.61; 95% CI = 0.39-0.94). High levels of sunshine exposure reduced risk of rectal cancer among those diagnosed when <60 years of age (OR = 0.62, 95% CI = 0.42-0.93). Examination of calcium in conjunction with VDR genotype showed that a significant 40% reduction in risk of rectal cancer was observed for the SS or BB VDR genotypes when calcium intake was low (p interaction = 0.01 for calcium interaction). For colon cancer, high levels of dietary intake of calcium, vitamin D, and low-fat dairy products reduced risk of cancer for the SS or BB VDR genotypes, although the p for interaction was not statistically significant. These data support previous observations that high levels of calcium and vitamin D reduce risk of rectal cancer and provide support for a weak protective effect for the SS and BB VDR genotypes. The risk associated with VDR genotype seems to depend upon the level of dietary calcium and vitamin D and tumor site.

Adult↗

PubMed2002

Rickets in VDR null mice is secondary to decreased apoptosis of hypertrophic chondrocytes.

Both vitamin D deficiency and the absence of a functional vitamin D receptor (VDR) lead to a growth plate abnormality known as rickets. Prevention of abnormal mineral ion homeostasis by early institution of dietary therapy in VDR null mice prevents rickets, demonstrating that the VDR is not required for normal growth plate maturation. We, therefore, hypothesized that rickets, in the absence of a functional VDR, is due to impaired mineral ion homeostasis. Analyses of growth plate morphology in VDR null mice demonstrated normal resting and proliferating chondrocyte layers; however an expansion of the hypertrophic chondrocyte layer was present by 24 days of age. Because extracellular calcium has been shown to play a role in chondrocyte maturation, we addressed the hypothesis that hypocalcemia led to impaired chondrocyte differentiation. However, in situ hybridization analyses revealed normal expression of hypertrophic chondrocyte markers in the tibial growth plate of 24 day old VDR null mice, suggesting that the increase in the hypertrophic chondrocyte layer was not secondary to impaired differentiation. We then addressed whether expansion of the hypertrophic chondrocyte layer was secondary to increased proliferation or decreased apoptosis. BrdU labeling failed to demonstrate an increase in chondrocyte proliferation in the VDR null mice; however, apoptosis was markedly diminished in the late hypertrophic chondrocytes of the VDR null mice, suggesting that impairment in programmed cell death of these cells leads to the characteristic findings of rickets.

Animals↗

PubMed2005

Large-scale population-based study shows no evidence of association between common polymorphism of the VDR gene and BMD in British women.

UNLABELLED: The VDR is a candidate gene for osteoporosis. Here we studied five common polymorphisms of VDR in relation to calcium intake and vitamin D status in a population-based cohort of 3100 British women, but found no significant association with bone mass, bone loss, or fracture. INTRODUCTION: Population studies of vitamin D receptor (VDR) polymorphisms have produced conflicting results. We performed a comprehensive study dealing with all potential confounders in a large population to determine whether polymorphisms in the VDR gene influence bone health. MATERIALS AND METHODS: We studied 3100 women (50-63 years old) with bone markers, 25-hydroxyvitamin D, calcium, PTH, diet, and physical activity collected in 1998-2000. BMD was measured in 1990-1994 and 1998-2000. Fracture prevalence was assessed in 2002. Women were genotyped for five polymorphisms in the VDR gene: Cdx-2, Fok1, Bsm1, Apa1, and Taq1. The relationship between VDR and BMD, and interactions between VDR genotype, dietary calcium, and 25-hydroxyvitamin D, were examined using analysis of covariance. RESULTS: Compared with carriers of the G allele, homozygotes for the rare Cdx-2 A polymorphism (n = 136) had less bone loss (-0.5 +/- 1.2 versus -0.7 +/- 1.0%/year [SD]; p = 0.01) and lower PTH (3.0 +/- 1.6 versus 3.4 +/- 2.0 pM; p = 0.03) despite similar vitamin D status. The association was not significant after correction for multiple testing or adjustment for confounders. At low calcium intakes, AA homozygotes had greater femoral neck (FN) BMD compared with carriers of the G allele, but at higher calcium intakes, the association was reversed. At low calcium intake, homozygotes for the b allele of Bsm1 had greater BMD compared with carriers of the B allele, but at higher calcium intakes, there was no difference. Similar results were seen for the Taq1 polymorphism. There was no evidence of gene-nutrient interaction when adjusted for body weight. No interactions between genotypes and vitamin D status on BMD were observed. CONCLUSIONS: VDR does not seem to influence BMD or bone turnover in early postmenopausal white women with adequate calcium intake. Gene-nutrient interactions on BMD may be an indirect consequence of interactions between genotype and calcium intake on weight.

Alleles↗