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

Abstract

FIG. 1. 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 D 3 , obtained from diet or derived from sunlight-initiated photobiogenesis in skin, is converted via two hydroxylation reactions to the 1,25(OH) 2 D 3 hormonal form that circulates in blood.The final step in bioactivation of vitamin to hormone is catalyzed by the renal 1-OHase when stimulated by PTH under conditions of low calcium.(Lower portion) Integrated actions of the 1,25(OH) 2 D 3 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) 2 D 3 -VDR in skin cell differentiation.(Top center) Conversion of 1,25(OH) 2 D 3 or the preceding 25(OH)D 3 metabolite to 24-hydroxylated forms in response to 1,25(OH) 2 D 3 -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 PO 4 enhances the synthesis of 1,25(OH) 2 D 3 , which then acts through VDR to effect phosphate reclamation by suppressing PTH as well as inducing NPT2 and PEX gene expression.NPT2 acts directly to reabsorb PO 4 , while the PEX enzyme eliminates phosphatonin.(Top right) Tumor-induced osteomalacia and XLH each elicit increased phosphatonin, an uncharacterized phosphaturic hormone that is postulated to inhibit both NPT2 and the 1-OHase, to cause severe phosphate wasting.