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

Abstract

ABSTRACT:The vitamin D hormone, 1,25-dihydroxyvitamin D 3 [1,25(OH) 2 D 3 ], binds with high affinity to the nuclear vitamin D receptor (VDR), which recruits its retinoid X receptor (RXR) heterodimeric partner to recognize vitamin D 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 the intestine and kidney. Fibroblast growth factor 23 (FGF23) is a phosphaturic hormone produced in osteoblasts that, like PTH, lowers serum phosphate by inhibiting renal reabsorption through Npt2a/Npt2c. Real-time PCR and reporter gene transfection assays were used to probe VDR-mediated transcriptional control by 1,25(OH) 2 D 3 . Reporter gene and mammalian two-hybrid transfections, plus competitive receptor binding assays, were used to discover novel VDR ligands. 1,25(OH) 2 D 3 induces FGF23 78-fold in osteoblasts, and because FGF23 in turn represses 1,25(OH) 2 D 3 synthesis, a reciprocal relationship is established, with FGF23 indirectly curtailing 1,25(OH) 2 D 3 -mediated intestinal absorption and counterbalancing renal reabsorption of phosphate, thereby reversing hyperphosphatemia and preventing ectopic calcification. Therefore, a 1,25(OH) 2 D 3 -FGF23 axis regulating phosphate is comparable in importance to the 1,25(OH) 2 D 3 -PTH axis that regulates calcium. 1,25(OH) 2 D 3 also elicits regulation of LRP5, Runx2, PHEX, TRPV6, and Npt2c, all anabolic toward bone, and RANKL, which is catabolic. Regulation of mouse RANKL by 1,25(OH) 2 D 3 supports a cloverleaf model, whereby VDR-RXR heterodimers bound to multiple VDREs are juxtapositioned through chromatin looping to form a supercomplex, potentially allowing simultaneous interactions with multiple co-modulators and chromatin remodeling enzymes. VDR also selectively binds certain 3/6 polyunsaturated fatty acids (PUFAs) with low affinity, leading to transcriptionally active VDR-RXR complexes. Moreover, the turmeric-derived polyphenol, curcumin, activates transcription of a VDRE reporter construct in human colon cancer cells. Activation of VDR by PUFAs and curcumin may elicit unique, 1,25(OH) 2 D 3 -independent signaling pathways to orchestrate the bioeffects of these lipids in intestine, bone, skin/hair follicle, and other VDR-containing tissues.

Long-chain polyunsaturated fatty acids: Selected mechanisms of action on bone

“…PPARs bind to DNA as an obligate heterodimer together with one of the retinoid X receptors (RXR) [132,133]. The PPARs exist as the PPAR isoforms α, β/δ and γ.…”

Prognostic Role of Vitamin D Status and Efficacy of Vitamin D Supplementation in Cancer Patients: A Systematic Review

“…The hormonal activity of vitD is mediated by its binding with vitD receptor (VDR) within the cell nuclei [1]. Because VDR is expressed in all body tissues, vitD also has extraskeletal effects.…”

Vitamin D and Human Pregnancy

“…In proximal tubule cells a complex of 25OHD-DBP-megalin is internalized through endocytosis, thereby providing substrate for the renal CYP27B1 19 . The 1,25(OH) 2 D synthesized in the kidney from 25OHD does D response element DNA motifs within gene promoters 21 . VDR-mediated responses also provide another level of feedback control for the vitamin D system, with serum 1,25(OH) 2 D acting to negatively regulate production of PTH 21 .…”

“…The 1,25(OH) 2 D synthesized in the kidney from 25OHD does D response element DNA motifs within gene promoters 21 . VDR-mediated responses also provide another level of feedback control for the vitamin D system, with serum 1,25(OH) 2 D acting to negatively regulate production of PTH 21 . Moreover, in another feedback control mechanism, 1,25(OH) 2 D stimulates expression of fibroblast growth factor 23 (FGF23) in bone, with the resulting rise in serum FGF23 acting as a potent suppressor of renal CYP27B1 expression 22 (see Figure 1).…”