The Nuclear Vitamin D Receptor: Biological and Molecular Regulatory Properties Revealed

Abstract

In the decade since the vitamin D receptor (VDR) was cloned1 and recognized as a member of the superfamily of nuclear receptors that regulate gene expression in a ligand-dependent manner,2, 3 the central role of VDR in the biology of vitamin D action has been illuminated and is being defined at the molecular level. Following renal production as the hormonal metabolite of vitamin D, 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3) functions as the ligand for VDR, with the hormone–receptor complex inducing calcemic and phosphatemic effects that result in normal bone mineralization and remodeling. VDR not only mediates the action of 1,25(OH)2D3 in calcium/phosphate translocating tissues, primarily intestine, but also elicits a myriad of apparent bioactivities in other major cell systems in the organism, including immune, neural, epithelial, and endocrine. The scope of this review will be limited to highlighting the actions of 1,25(OH)2D3 mediated by nuclear VDR and discussing new developments in the structure/function analysis of the receptor, including the phenotype of VDR knockout mice and the biochemical classification of patients with point mutations in the receptor. These new advances, along with other recent research, will be interpreted to update our understanding of the molecular role of VDR, ranging from characterization of its natural gene and clinically significant polymorphisms, through its DNA contact sites and protein partners, to novel ligand analogs that hold the promise of influencing VDR conformation in a therapeutically beneficial fashion. The traditional action of vitamin D, via its 1,25(OH)2D3 hormonal metabolite, is to effect calcium and phosphate homeostasis to ensure the deposition of bone mineral (summarized in Fig. 1A). 1,25(OH)2D3 stimulates intestinal calcium and phosphate absorption, bone calcium and phosphate resorption, and renal calcium and phosphate reabsorption, thus increasing the blood Ca•PO4 ion product. Failure to achieve normal bone mineral accretion by these mechanisms leads to rachitic syndromes. Nutritional rickets, caused by the simultaneous deprivation of sunlight exposure4 and dietary vitamin D, was ameliorated in classic experiments by administration of this fat soluble vitamin (reviewed in Ref. 5). Subsequently, it was recognized that the pathways comprising the metabolic activation of the vitamin to its hormonal form and consequent functions of the hormone in target tissues (Fig. 1) present additional steps where defects directly elicit vitamin D–resistant rachitic syndromes. Two such disorders involve the inadequate bioactivation of 25-hydroxyvitamin D3 (25(OH)D3), a constitutively produced intermediary metabolite, to 1,25- (OH)2D3. This step is catalyzed by the 1α-OHase enzyme in kidney (Fig. 1A). Chronic renal failure results in renal rickets and secondary hyperparathyroidism when compromised renal mass reduces 1α-OHase activity,6 whereas pseudo–vitamin D–deficiency rickets (PDDR) involves a specific hereditary defect in the gene coding for the 1α-OHase enzyme.7 The latter conclusion has been verified by the recent cloning of cDNAs for the rat8 and mouse9 1α-OHase P450 and the pinpointing of the human 1α-OHase gene to a chromosomal locus coincident with PDDR.8 Interestingly, the 1α-OHase/PDDR locus maps rather closely to the VDR gene on chromosome 12 in the 12q13–14 region,7 a proximity that may be relevant to the evolution and control of the vitamin D ligand–receptor system. Calcemic and phosphatemic biological actions of vitamin D in mammals. (A) Effects of vitamin D and its metabolites to ensure skeletal integrity, especially when calcium is limiting. (Central open box) Vitamin D3, obtained from diet or derived from sunlight-initiated photobiogenesis in skin, is converted via two hydroxylation reactions to the 1,25(OH)2D3 hormonal form that circulates in blood. The final step in bioactivation of vitamin to hormone is catalyzed by the renal 1α-OHase when stimulated by PTH under conditions of low calcium. (Lower portion) Integrated actions of the 1,25(OH)2D3 metabolite, via binding to the intracellular VDR, to control calcium homeostasis in bone, intestine, kidney, and parathyroid as explained in the text. (Top left) Action of 1,25(OH)2D3–VDR in skin cell differentiation. (Top center) Conversion of 1,25(OH)2D3 or the preceding 25(OH)D3 metabolite to 24-hydroxylated forms in response to 1,25(OH)2D3–VDR induction of the 24-OHase gene. This conversion serves to initiate catabolism of the vitamin D molecule, but may also produce 24-hydroxylated metabolites with novel hormonal activity with respect to chondrocyte differentiation and bone mineralization (see text). (B) The vitamin D bioactivation-phosphate homeostatic loop: proposed novel roles for phosphatonin, the PEX gene product, and NPT2. (Left and lower portion) Under normal physiologic conditions, low PO4 enhances the synthesis of 1,25(OH)2D3, which then acts through VDR to effect phosphate reclamation by suppressing