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

Research output: Contribution to journalArticle

296 Citations (Scopus)

Abstract

The hormonal metabolite of vitamin D, 1α,25-dihydroxyvitamin D 3 (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.

Original languageEnglish (US)
Pages (from-to)77-98
Number of pages22
JournalCalcified Tissue International
Volume92
Issue number2
DOIs
StatePublished - 2013

Fingerprint

Calcitriol Receptors
Vitamin D
Retinoid X Receptors
Ligands
Claudin-2
Lithocholic Acid
Calcium
Co-Repressor Proteins
Proteins
Osteopontin
Curcumin
Docosahexaenoic Acids
Bone Remodeling
Osteocalcin
Intestinal Absorption
1,25-dihydroxyvitamin D
Keratinocytes
Type 2 Diabetes Mellitus
Genes
Osteoporosis

Keywords

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

ASJC Scopus subject areas

  • Orthopedics and Sports Medicine
  • Endocrinology, Diabetes and Metabolism
  • Endocrinology

Cite this

Molecular mechanisms of vitamin D action. / Haussler, Mark R; Whitfield, G Kerr; Kaneko, Ichiro; Haussler, Carol A.; Hsieh, David; Hsieh, Jui-Cheng; Jurutka, Peter W.

In: Calcified Tissue International, Vol. 92, No. 2, 2013, p. 77-98.

Research output: Contribution to journalArticle

Haussler, Mark R ; Whitfield, G Kerr ; Kaneko, Ichiro ; Haussler, Carol A. ; Hsieh, David ; Hsieh, Jui-Cheng ; Jurutka, Peter W. / Molecular mechanisms of vitamin D action. In: Calcified Tissue International. 2013 ; Vol. 92, No. 2. pp. 77-98.
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