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

J Steroid Biochem Mol Biol. 2010 Jul;121(1-2):88-97. doi: 10.1016/j.jsbmb.2010.03.019. Epub 2010 Mar 20.

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 beta-catenin, ligand-dependently blunting beta-catenin mediated transcription in colon cancer cells to attenuate growth, while potentiating beta-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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Aging*
  • Animals
  • Calcium / metabolism
  • Cell Nucleus / metabolism*
  • Gene Expression Regulation*
  • Humans
  • Keratinocytes / cytology
  • Mice
  • Models, Biological
  • Osteopontin / metabolism
  • Phosphates / metabolism
  • Receptors, Calcitriol / metabolism*
  • Signal Transduction
  • Wnt Proteins / metabolism
  • beta Catenin / metabolism

Substances

  • Phosphates
  • Receptors, Calcitriol
  • Wnt Proteins
  • beta Catenin
  • Osteopontin
  • Calcium