Vitamin D receptor: Key roles in bone mineral pathophysiology, molecular mechanism of action, and novel nutritional ligands

Peter Jurutka, Leonid Bartik, G. Kerr Whitfield, Douglas R. Mathern, Thomas K. Barthel, Miriam Gurevich, Jui Cheng Hsieh, Magdalena Kaczmarska, Carol A. Haussler, Mark R. Haussler

Research output: Contribution to journalArticle

100 Scopus citations

Abstract

The vitamin D hormone, 1,25-dihydroxyvitamin D3 [1,25(OH) 2D3], 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)2D3 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) 2D3. Reporter gene and mammalian two-hybrid transfections, plus competitive receptor binding assays, were used to discover novel VDR ligands. 1,25(OH)2D3 induces FGF23 78-fold in osteoblasts, and because FGF23 in turn represses 1,25(OH)2D3 synthesis, a reciprocal relationship is established, with FGF23 indirectly curtailing 1,25(OH)2D3-mediated intestinal absorption and counterbalancing renal reabsorption of phosphate, thereby reversing hyperphosphatemia and preventing ectopic calcification. Therefore, a 1,25(OH)2D3-FGF23 axis regulating phosphate is comparable in importance to the 1,25(OH)2D3-PTH axis that regulates calcium. 1,25(OH)2D3 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)2D3 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 ω3/ω6 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)2D3-independent signaling pathways to orchestrate the bioeffects of these lipids in intestine, bone, skin/hair follicle, and other VDR-containing tissues.

Original languageEnglish (US)
Pages (from-to)V2-V10
JournalJournal of Bone and Mineral Research
Volume22
Issue numberSUPPL. 2
DOIs
StatePublished - Dec 1 2007

Keywords

  • Bone mineral homeostasis
  • Curcumin
  • Essential fatty acids
  • Fibroblast growth factor 23
  • RANKL
  • Vitamin D

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Orthopedics and Sports Medicine

Fingerprint Dive into the research topics of 'Vitamin D receptor: Key roles in bone mineral pathophysiology, molecular mechanism of action, and novel nutritional ligands'. Together they form a unique fingerprint.

  • Cite this

    Jurutka, P., Bartik, L., Whitfield, G. K., Mathern, D. R., Barthel, T. K., Gurevich, M., Hsieh, J. C., Kaczmarska, M., Haussler, C. A., & Haussler, M. R. (2007). Vitamin D receptor: Key roles in bone mineral pathophysiology, molecular mechanism of action, and novel nutritional ligands. Journal of Bone and Mineral Research, 22(SUPPL. 2), V2-V10. https://doi.org/10.1359/jbmr.07s216