Calcified Tissue International

, Volume 92, Issue 2, pp 77–98

Molecular Mechanisms of Vitamin D Action

  • Mark R. Haussler
  • G. Kerr Whitfield
  • Ichiro Kaneko
  • Carol A. Haussler
  • David Hsieh
  • Jui-Cheng Hsieh
  • Peter W. Jurutka
Original Paper

DOI: 10.1007/s00223-012-9619-0

Cite this article as:
Haussler, M.R., Whitfield, G.K., Kaneko, I. et al. Calcif Tissue Int (2013) 92: 77. doi:10.1007/s00223-012-9619-0

Abstract

The hormonal metabolite of vitamin D, 1α,25-dihydroxyvitamin D3 (1,25D), initiates biological responses via binding to the vitamin D receptor (VDR). When occupied by 1,25D, VDR interacts with the retinoid X receptor (RXR) to form a heterodimer that binds to vitamin D responsive elements in the region of genes directly controlled by 1,25D. By recruiting complexes of either coactivators or corepressors, ligand-activated VDR-RXR modulates the transcription of genes encoding proteins that promulgate the traditional functions of vitamin D, including signaling intestinal calcium and phosphate absorption to effect skeletal and calcium homeostasis. Thus, vitamin D action in a particular cell depends upon the metabolic production or delivery of sufficient concentrations of the 1,25D ligand, expression of adequate VDR and RXR coreceptor proteins, and cell-specific programming of transcriptional responses to regulate select genes that encode proteins that function in mediating the effects of vitamin D. For example, 1,25D induces RANKL, SPP1 (osteopontin), and BGP (osteocalcin) to govern bone mineral remodeling; TRPV6, CaBP9k, and claudin 2 to promote intestinal calcium absorption; and TRPV5, klotho, and Npt2c to regulate renal calcium and phosphate reabsorption. VDR appears to function unliganded by 1,25D in keratinocytes to drive mammalian hair cycling via regulation of genes such as CASP14, S100A8, SOSTDC1, and others affecting Wnt signaling. Finally, alternative, low-affinity, non-vitamin D VDR ligands, e.g., lithocholic acid, docosahexaenoic acid, and curcumin, have been reported. Combined alternative VDR ligand(s) and 1,25D/VDR control of gene expression may delay chronic disorders of aging such as osteoporosis, type 2 diabetes, cardiovascular disease, and cancer.

Keywords

Coactivator Corepressor 1α,25-Dihydroxyvitamin D3 Retinoid X receptor Transcription Vitamin D receptor Vitamin D responsive element 

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Mark R. Haussler
    • 1
  • G. Kerr Whitfield
    • 1
  • Ichiro Kaneko
    • 1
    • 2
  • Carol A. Haussler
    • 1
  • David Hsieh
    • 1
  • Jui-Cheng Hsieh
    • 1
  • Peter W. Jurutka
    • 1
    • 2
  1. 1.Department of Basic Medical SciencesUniversity of Arizona College of Medicine-PhoenixPhoenixUSA
  2. 2.Division of Mathematical and Natural SciencesArizona State UniversityPhoenixUSA