The nuclear vitamin D receptor controls the expression of genes encoding factors which feed the " Fountain of Youth" to mediate healthful aging

Mark R. Haussler, Carol A. Haussler, G. Kerr Whitfield, Jui Cheng Hsieh, Paul D. Thompson, Thomas K. Barthel, Leonid Bartik, Jan B. Egan, Yifei Wu, Jana L. Kubicek, Christine L. Lowmiller, Eric W. Moffet, Ryan E. Forster, Peter Jurutka

Research output: Contribution to journalArticle

124 Scopus citations

Abstract

The nuclear vitamin D receptor (VDR) binds 1,25-dihydroxyvitamin D3 (1,25D), its high affinity renal endocrine ligand, to signal intestinal calcium and phosphate absorption plus bone remodeling, generating a mineralized skeleton free of rickets/osteomalacia with a reduced risk of osteoporotic fractures. 1,25D/VDR signaling regulates the expression of TRPV6, BGP, SPP1, LRP5, RANKL and OPG, while achieving feedback control of mineral ions to prevent age-related ectopic calcification by governing CYP24A1, PTH, FGF23, PHEX, and klotho transcription. Vitamin D also elicits numerous intracrine actions when circulating 25-hydroxyvitamin D3, the metabolite reflecting vitamin D status, is converted to 1,25D locally by extrarenal CYP27B1, and binds VDR to promote immunoregulation, antimicrobial defense, xenobiotic detoxification, anti-inflammatory/anticancer actions and cardiovascular benefits. VDR also affects Wnt signaling through direct interaction with β-catenin, ligand-dependently blunting β-catenin mediated transcription in colon cancer cells to attenuate growth, while potentiating β-catenin signaling via VDR ligand-independent mechanisms in osteoblasts and keratinocytes to function osteogenically and as a pro-hair cycling receptor, respectively. Finally, VDR also drives the mammalian hair cycle in conjunction with the hairless corepressor by repressing SOSTDC1, S100A8/S100A9, and PTHrP. Hair provides a shield against UV-induced skin damage and cancer in terrestrial mammals, illuminating another function of VDR that facilitates healthful aging.

Original languageEnglish (US)
Pages (from-to)88-97
Number of pages10
JournalJournal of Steroid Biochemistry and Molecular Biology
Volume121
Issue number1-2
DOIs
StatePublished - Jul 2010

Keywords

  • 1,25-Dihydroxyvitamin D
  • CYP24A1
  • Calcium metabolism
  • Fibroblast growth factor 23
  • Hairless
  • Klotho
  • LRP5
  • OPG
  • Osteocalcin (BGP)
  • Osteopontin (SSP1)
  • Phosphate metabolism
  • RANKL
  • S100A8
  • SOSTDC1
  • TRPV6
  • Vitamin D receptor
  • β-Catenin

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Endocrinology
  • Clinical Biochemistry
  • Cell Biology

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  • Cite this

    Haussler, M. R., Haussler, C. A., Whitfield, G. K., Hsieh, J. C., Thompson, P. D., Barthel, T. K., Bartik, L., Egan, J. B., Wu, Y., Kubicek, J. L., Lowmiller, C. L., Moffet, E. W., Forster, R. E., & Jurutka, P. (2010). The nuclear vitamin D receptor controls the expression of genes encoding factors which feed the " Fountain of Youth" to mediate healthful aging. Journal of Steroid Biochemistry and Molecular Biology, 121(1-2), 88-97. https://doi.org/10.1016/j.jsbmb.2010.03.019