Vitamin D Receptor: Key Roles in Bone Mineral Pathophysiology, Molecular Mechanism of Action, and Novel Nutritional Ligands

摘要: The vitamin D hormone, 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)], binds with high affinity to the nuclear receptor (VDR), which recruits its retinoid X (RXR) heterodimeric partner recognize responsive elements (VDREs) in target genes. 1,25(OH)(2)D(3) is known primarily as a regulator of calcium, but it also controls phosphate (re)absorption at intestine and kidney. Fibroblast growth factor 23 (FGF23) phosphaturic hormone produced osteoblasts that, like PTH, lowers serum by inhibiting renal reabsorption through Npt2a/Npt2c. Real-time PCR reporter gene transfection assays were used probe VDR-mediated transcriptional control 1,25(OH)(2)D(3). Reporter mammalian two-hybrid transfections, plus competitive binding assays, discover novel VDR ligands. induces FGF23 78-fold osteoblasts, because turn represses synthesis, reciprocal relationship established, indirectly curtailing 1,25(OH)(2)D(3)-mediated intestinal absorption counterbalancing phosphate, thereby reversing hyperphosphatemia preventing ectopic calcification. Therefore, 1,25(OH)(2)D(3)-FGF23 axis regulating comparable importance 1,25(OH)(2)D(3)-PTH that regulates calcium. elicits regulation LRP5, Runx2, PHEX, TRPV6, Npt2c, all anabolic toward bone, RANKL, catabolic. Regulation mouse RANKL supports cloverleaf model, whereby VDR-RXR heterodimers bound multiple VDREs are juxtapositioned chromatin looping form supercomplex, potentially allowing simultaneous interactions co-modulators remodeling enzymes. selectively certain omega3/omega6 polyunsaturated fatty acids (PUFAs) low affinity, leading transcriptionally active complexes. Moreover, turmeric-derived polyphenol, curcumin, activates transcription VDRE construct human colon cancer cells. Activation PUFAs curcumin may elicit unique, 1,25(OH)(2)D(3)-independent signaling pathways orchestrate bioeffects these lipids intestine, skin/hair follicle, other VDR-containing tissues.