Disease relevance of Vdr

• Vdr null mice were profoundly hypocalcemic, conceived infrequently, and had significantly fewer viable fetuses in utero that were also of lower body weight [1].
• Studies in kindreds with VDR mutations (vitamin D-dependent rickets type II, VDDR II) have demonstrated hypocalcemia, hyperparathyroidism, rickets, and osteomalacia [2].
• We found that VDR-/- mice show mild hypocalcemia, clear rickets and osteomalacia on bone histomorphometry, lower cortical bone density on quantitative tomography, and reduced concentrations of calbindin-D9k (CaBP-D9k) in duodenal mucosa and kidney [3].
• To genetically separate the effects of phosphate and vitamin D on Fgf23, we examined vitamin D receptor null (VDR(-/-)) mice, which are hypocalcemic and hypophosphatemic secondary to hyperparathyroidism [4].
• This study was performed to determine the effect of VDR deficiency on immune function and inflammation of the gastrointestinal tract in a model of inflammatory bowel disease, namely interleukin-10 (IL-10) knockout mice [5].
• Absence of the VDR impairs canonical Wnt signaling in keratinocytes and leads to the development of alopecia due to a defect in keratinocyte stem cells [6].

Psychiatry related information on Vdr

• Here we report that VDR mutants display unaffected depressive-like behaviour, but show abnormal social behaviours, reduced social barbering and aggressiveness, impaired nest building and aberrant maternal (pup neglect, cannibalism) behaviours [7].

High impact information on Vdr

• The findings establish a critical role for VDR in growth, bone formation and female reproduction in the post-weaning stage [8].
• However, the molecular basis for the actions of 1 alpha,25(OH)2D3 in bone formation, its role during development and VDR genetic polymorphisms for predicting bone mineral density are uncertain [8].
• We report here that in VDR null mutant mice, no defects in development and growth were observed before weaning, irrespective of reduced expression of vitamin D target genes [8].
• Mice lacking the vitamin D receptor exhibit impaired bone formation, uterine hypoplasia and growth retardation after weaning [8].
• The transcription factor SNAIL represses vitamin D receptor expression and responsiveness in human colon cancer [9].

Chemical compound and disease context of Vdr

• Treatment with the HCa-Lac diet containing 2% calcium, 1.5% phosphorus and 20% lactose reversed the hypocalcemia seen in adult VDR-null mice in 3 weeks but did not significantly change the blood ionized calcium in wild-type mice [10].
• Steroid and xenobiotic receptor and vitamin D receptor crosstalk mediates CYP24 expression and drug-induced osteomalacia [11].
• We show here that renin expression and plasma angiotensin II production were increased severalfold in vitamin D receptor-null (VDR-null) mice, leading to hypertension, cardiac hypertrophy, and increased water intake [12].
• Inhibition of proliferation and induction of apoptosis by 25-hydroxyvitamin D3-3beta-(2)-Bromoacetate, a nontoxic and vitamin D receptor-alkylating analog of 25-hydroxyvitamin D3 in prostate cancer cells [13].
• From 12 months of age on, MMTV-neu mice lacking VDR also experience body weight loss, atrophy of the mammary fat pad, estrogen deficiency and reduced survival [14].

Biological context of Vdr

• Vitamin D, the major steroid hormone that controls mineral ion homeostasis, exerts its actions through the vitamin D receptor (VDR) [2].
• These results indicate that this 24-bp sequence containing two 9-bp motifs binds to the vitamin D receptor and mediates the vitamin D3 enhancement of murine Spp-1 gene expression [15].
• We have generated a mouse model of VDDR II by targeted ablation of the second zinc finger of the VDR DNA-binding domain [2].
• These regions contained binding sites for not only VDR and RXR, but also the glucocorticoid receptor (GR) [16].
• The active metabolite 1,25(OH)2D has its effects through the vitamin D receptor leading to gene expression, e.g. the calcium binding protein or osteocalcin or through a plasma membrane receptor and second messengers such as cyclic AMP [17].

Anatomical context of Vdr

• Supplementation of a calcium-enriched diet increased the rate of conception in Vdr nulls but did not normalize the number or weight of viable fetuses [1].
• These experiments have demonstrated that for active calcium absorption, longitudinal bone growth and the activity of osteoblasts and osteoclasts both 1,25(OH)2D and the vitamin D receptor are essential [17].
• Muscle cells contain vitamin D receptor and several studies have demonstrated that serum 25(OH)D is related to physical performance [17].
• Parathyroid gland size and the development of the cartilaginous growth plate were each regulated by calcium and by 1,25(OH)2D3 but independent of the VDR [18].
• We further show that this 1,25 D(3)-mediated inhibition of PIN was coincident with up-regulation of vitamin D receptor expression in the prostatic epithelium of the mutant mice, as well as in CASP prostate epithelial cell lines developed from these mice, while having no effect on androgen receptor expression or androgen receptor signaling [19].

Associations of Vdr with chemical compounds

• Vdr null fetuses did have threefold increased 1,25-dihydroxyvitamin D levels accompanied by increased 1alpha-hydroxylase mRNA in kidney but not placenta; a small increase was also noted in placental expression of parathyroid hormone-related protein (PTHrP) [1].
• After hydroxylation in the liver into 25-hydroxyvitamin D (25(OH)D) and kidney into 1,25-dihydroxyvitamin D (1,25(OH)2D), the active metabolite can enter the cell, bind to the vitamin D-receptor and subsequently to a responsive gene such as that of calcium binding protein [17].
• Functional analysis of a murine Mrp3 promoter reporter construct revealed vitamin D receptor (VDR)-dependent activation by 1,25-dihydroxyvitamin D(3) (VD3), 9-cis-retinoic acid (RA), and the cholestatic secondary bile acid, lithocholic acid (LCA) [20].
• 1,25-Dihydroxyvitamin D3 stimulates cyclic vitamin D receptor/retinoid X receptor DNA-binding, co-activator recruitment, and histone acetylation in intact osteoblasts [21].
• No synergistic interaction between dexamethasone and D3 on either vitamin D receptor or GR mRNA expression was noted [22].

Physical interactions of Vdr

• Gel retardation assays with ROS 17/2.8 nuclear extracts suggest that the VDR binds to the mouse osteopontin VDRE predominantly as a heterodimer with retinoid X receptor(s) (RXR(s)) [23].

Regulatory relationships of Vdr

• Vitamin D receptor is required to control gastrointestinal immunity in IL-10 knockout mice [5].
• Vitamin D receptor is required for dietary calcium-induced repression of calbindin-D9k expression in mice [10].
• Zymography and RT-PCR showed that MMP-2 and MMP-9 were up regulated in VDR KO mice [24].
• Thus, our findings indicate that WINAC associates with chromatin through a physical interaction between the WSTF bromodomain and acetylated his tones, which appears to be indispensable for VDR/promoter association for ligand-induced transrepression of 1alpha(OH)ase gene expression [25].
• These changes are associated with increased expression of Hr, suggesting a role for VDR in regulating Hr expression [26].

Other interactions of Vdr

• Vitamin D receptor-independent FGF23 actions in regulating phosphate and vitamin D metabolism [27].
• The skeletal response to pregnancy was comparable in wt and VDR-/- mice; duodenal CaBP-D9k concentrations increased during pregnancy in VDR-/- as in wt mice, but remained 40% lower than in wt mice [3].
• Chromatin immunoprecipitation (ChIP) from liver nuclei showed that aging had no effect on the activity of an IR0 enhancer in the Sult2A1 chromatin to recruit VDR, RXR-alpha (retinoid X receptor) and PXR in mice injected with D(3) or PCN [28].
• In addition, our data suggest that the 2% Ca diet promotes a vitamin D receptor-independent anabolic effect on bone formation and calcium absorption, leading to improved calcium balance even in the presence of high PTH levels [29].
• In this report, we examined the VDR- and PXR-mediated gene induction of the phase II sulfotransferase Sult2A1 in the livers of 4-month- and 20-month-old mice [28].

Analytical, diagnostic and therapeutic context of Vdr

• Targeted ablation of the vitamin D receptor: an animal model of vitamin D-dependent rickets type II with alopecia [2].
• To identify such mechanisms, we screened a DNA microarray which tiled across the entire mouse RankL gene locus at a 50-bp resolution using chromatin immunoprecipitation (ChIP)-derived DNA precipitated with antibodies to the vitamin D receptor (VDR) and the retinoid X receptor (RXR) [16].
• Levels of Hr were greater in the Vdr null mice compared to wildtype controls, results confirmed by quantitative RT-PCR [26].
• Ovariectomy caused no change in duodenal expression pattern of VDR WT and KO mice, whereas treatment with a pharmacologic dose of estrogens induced CaT1 mRNA expression in VDR WT (4-fold) and KO (8-fold) mice [30].
• In the present study, we used high-density oligonucleotide microarray to examine gene expression profile in wild type [WT] and vitamin D receptor knockout mice (VDR KO) which was further validated by RT-PCR [24].

References