Vitamin D Receptor Mediates a Myriad of Biological Actions Dependent on Its 1,25‐Dihydroxyvitamin D Ligand: Distinct Regulatory Themes Revealed by Induction of Klotho and Fibroblast Growth Factor‐23

Abstract

The hormonal vitamin D metabolite, 1,25‐dihydroxyvitamin D [1,25(OH)2D], produced in kidney, acts in numerous end organs via the nuclear vitamin D receptor (VDR) to trigger molecular events that orchestrate bone mineral homeostasis. VDR is a ligand‐controlled transcription factor that obligatorily heterodimerizes with retinoid X receptor (RXR) to target vitamin D responsive elements (VDREs) in the vicinity of vitamin D‐regulated genes. Circulating 1,25(OH)2D concentrations are governed by PTH, an inducer of renal D‐hormone biosynthesis catalyzed by CYP27B1 that functions as the key player in a calcemic endocrine circuit, and by fibroblast growth factor‐23 (FGF23), a repressor of the CYP27B1 renal enzyme, creating a hypophosphatemic endocrine loop. 1,25(OH)2D/VDR–RXR acts in kidney to induce Klotho (a phosphaturic coreceptor for FGF23) to correct hyperphosphatemia, NPT2a/c to correct hypophosphatemia, and TRPV5 and CaBP28k to enhance calcium reabsorption. 1,25(OH)2D‐liganded VDR–RXR functions in osteoblasts/osteocytes by augmenting RANK‐ligand expression to paracrine signal osteoclastic bone resorption, while simultaneously inducing FGF23, SPP1, BGLP, LRP5, ANK1, ENPP1, and TNAP, and conversely repressing RUNX2 and PHEX expression, effecting localized control of mineralization to sculpt the skeleton. Herein, we document the history of 1,25(OH)2D/VDR and summarize recent advances in characterizing their physiology, biochemistry, and mechanism of action by highlighting two examples of 1,25(OH)2D/VDR molecular function. The first is VDR‐mediated primary induction of Klotho mRNA by 1,25(OH)2D in kidney via a mechanism initiated by the docking of liganded VDR–RXR on a VDRE at −35 kb in the mouse Klotho gene. In contrast, the secondary induction of FGF23 by 1,25(OH)2D in bone is proposed to involve rapid nongenomic action of 1,25(OH)2D/VDR to acutely activate PI3K, in turn signaling the induction of MZF1, a transcription factor that, in cooperation with c‐ets1‐P, binds to an enhancer element centered at −263 bp in the promoter‐proximal region of the mouse fgf23 gene. Chronically, 1,25(OH)2D‐induced osteopontin apparently potentiates MZF1. © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Vitamin D Deficiency Is Significantly Associated with Retinopathy in Type 2 Diabetes Mellitus: A Case-Control Study

“…Vitamin D has been associated with different extraskeletal effects, due to the vitamin D receptor (VDR) being present in a wide variety of cells in the body [ 4 , 5 ] and influencing the regulation of more than 2000 genes [ 6 ]. While vitamin D deficiency has been associated with multiple diseases, not all of these associations have been verified [ 7 ].…”

Gene expression changes related to bone mineralization, blood pressure and lipid metabolism in mouse kidneys after space travel

“…Because previous studies observed Cyp24a1 induction and Cyp27b1 suppression in mouse kidneys during a stay in orbit, [6][7][8] our data indicate that the expression profile of vitamin D 3 regulators, which is modulated by the space-travel environment, is preserved for at least 2 days after the return to Earth. We also found reduced expression of the Bglap gene, which is known to be activated by vitamin D 3 signaling to produce the bone matrix protein osteocalcin, 31 in the bone of space-traveled mice (Figure 2b). The changes in Fgf23 and Bglap gene expression in the bone samples support the contention that active vitamin D 3 levels in the plasma are decreased by space travel, which results in bone mass reduction.…”

Pathobiology of the Klotho Antiaging Protein and Therapeutic Considerations

“…In rodents, however, there is clear evidence of Klotho enhancement by vitamin D ( Table2 ). To explain this therapeutic effect, the complex interactions underling FGF23/Klotho/vitamin D homeostasis must be considered, as recently reviewed ( Haussler et al, 2020 ; Neyra et al, 2021 ).…”

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