Cited by 761Vitamin D Research StudiesParathyroid Disorders and TreatmentsVitamin K Research Studies

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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.·2013·Calcified Tissue International

DOI 10.1007/s00223-012-9619-0

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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, CaBP(9k), 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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Authors: Haussler, M. R., Whitfield, G. K., Kaneko, I., Haussler, C. A., Hsieh, D., Hsieh, J.-C., & Jurutka, P. W.
Affiliations: University of Arizona College of Medicine- Phoenix (US)
University of Arizona (US)
Corresponding author: Haussler, Mark R.
ORCID: Haussler, Mark R.
Kaneko, Ichiro
Haussler, Carol A.
Hsieh, David
Hsieh, Jui-Cheng
Jurutka, Peter W.
Venue: Calcified Tissue International
Publisher: Springer Science and Business Media LLC
Published: 2012-07-11
Volume: 92
Issue: 2
Pages: 77-98
ISSN: 0171-967X (ISSN-L)
1432-0827
DOI: 10.1007/s00223-012-9619-0
OpenAlex: W2017851530
Cited by: 759
References: 132
Citations by year: 2026: 37 · 2025: 41 · 2024: 53 · 2023: 54 · 2022: 52 · 2021: 82 · 2020: 79 · 2019: 48 · 2018: 54 · 2017: 58 · 2016: 49 · 2015: 64 · 2014: 54 · 2013: 29 · 2012: 4
FWCI: 6.99
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
Locations: Calcified Tissue International (publishedVersion)
PubMed (publishedVersion)
Topics: Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Vitamin D Research Studies
Health Sciences › Medicine › Nephrology › Parathyroid Disorders and Treatments
Health Sciences › Nursing › Nutrition and Dietetics › Vitamin K Research Studies
Keywords: vitamin D, 1,25-dihydroxyvitamin D3, vitamin D receptor, retinoid X receptor, heterodimer, transcriptional regulation, calcium homeostasis, phosphate homeostasis, intestinal calcium absorption, bone remodeling, RANKL, osteocalcin, osteopontin, renal calcium reabsorption, hair cycle, keratinocytes, Wnt signaling, lithocholic acid, docosahexaenoic acid, curcumin, osteoporosis, type 2 diabetes, cardiovascular disease, cancer
MeSH terms: Animals, Gene Expression Regulation, Humans, Vitamin D, Signal Transduction, Receptors, Calcitriol

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