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Calcified Tissue International
Published in: Calcified Tissue International 2/2013

01-02-2013 | Original Paper

Molecular Mechanisms of Vitamin D Action

Authors: Mark R. Haussler, G. Kerr Whitfield, Ichiro Kaneko, Carol A. Haussler, David Hsieh, Jui-Cheng Hsieh, Peter W. Jurutka

Published in: Calcified Tissue International | Issue 2/2013

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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.
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Metadata
Title
Molecular Mechanisms of Vitamin D Action
Authors
Mark R. Haussler
G. Kerr Whitfield
Ichiro Kaneko
Carol A. Haussler
David Hsieh
Jui-Cheng Hsieh
Peter W. Jurutka
Publication date
01-02-2013
Publisher
Springer-Verlag
Published in
Calcified Tissue International / Issue 2/2013
Print ISSN: 0171-967X
Electronic ISSN: 1432-0827
DOI
https://doi.org/10.1007/s00223-012-9619-0

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