Biology and Mechanisms of Action of the Vitamin D Hormone

Abstract

The central role of hormonal 1,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃] is to regulate calcium and phosphorus homeostasis via actions in intestine, kidney, and bone. These and other actions in many cell types not involved in mineral metabolism are mediated by the vitamin D receptor. Recent studies using genome-wide scale techniques have extended fundamental ideas regarding vitamin D-mediated control of gene expression while simultaneously revealing a series of new concepts. This article summarizes the current view of the biological actions of the vitamin D hormone and focuses on new concepts that drive the understanding of the mechanisms through which vitamin D operates.

Keywords: Calcemic hormones; Genetic linkage; Genome-wide principles; Mineral homeostasis; RANKL; Target genes; Transcription; Transient receptor potential vanilloid type-6 (TRPV6).

Figure 1

Sunlight mediated photolysis of 7-dehydrocholesterol to vitamin D in the skin, and its activation through subsequent sequential hydroxylation in the liver by Cyp2R1 to 25(OH)D₃ and by Cyp27b1 to the vitamin D hormone 1,25(OH)₂D₃ in the kidney. Cyp24a1 initiates the degradation of 25(OH)D₃ to 24,25(OH)₂D₃ in the kidney and the degradation of 1,25(OH)₂D₃ to 1,24,25(OH)₃D₃ in all vitamin D targets tissues that results in eventual conversion to calcitroic acid. Alternative degradation pathways in mice also result from Cyp24a1 activity as well.

Figure 2

Scheme for the regulation of mineral homeostasis in higher vertebrates. The hormones PTH and FGF23 monitor extracellular calcium and phosphate, respectively, and orchestrate the mineral regulating activities of the intestine, kidney and bone through actions on vitamin D metabolism.

Figure 3

General mechanisms of action of 1,25(OH)₂D₃ and its diverse biology in target cells. 1,25(OH)₂D₃ regulates gene transcription in target cells by binding to VDR. This activated VDR heterodimerizes with RXR and binds to VDREs (vitamin D response elements) in and around target genes. Transcription proceeds through the interaction of the VDR with coactivators and with the transcription machinery. Liganded VDR interacts with steroid receptor coactivator 2 (SRC2; also known as GRIP1), which has histone acetylase activity (HAT), as a primary coactivator. SRC2 can recruit proteins as secondary coactivators such as CBP/p300 which also have HAT activity. VDR also interacts with mediator complex, which facilitates the activation of the RNA polymerase II holoenzyme through its C-terminal domain (CTD), thus promoting formation of the preinitiation complex. The SWI/SNF complex, which remodels chromatin using the energy of ATP hydrolysis, also contributes to activation by VDR. 1,25(OH)₂D₃ is known to maintain calcium homeostasis and to affect numerous other cell types. Effects on other cells systems include inhibition of proliferation of cancer cells and modulation of the immune system.

Figure 4

Mechanism of suppression of the IL-17 gene by 1,25(OH)₂D₃. Mechanism of repression of IL-17A activated transcription by 1,25(OH)₂D₃. The negative effect of 1,25(OH)₂D₃ on IL-17A involves blocking NFAT (an essential regulator of IL-17A gene transcription) from binding to its sites on the IL-17 gene and 1,25(OH)₂D₃ dependent association of RXR/VDR with the NFAT elements. 1,25(OH)₂D₃ repression of IL-17A also involves 1,25(OH)₂D₃ mediated recruitment of histone deacetylase and sequestration of Runx1 (also an important T cell receptor mediated transcriptional regulator of IL-17A) by 1,25(OH)₂D₃/VDR (not shown). From Joshi S, Pantalena LC, Liu XK, et al. 1,25-dihydroxyvitamin D(3) ameliorates Th17 autoimmunity via transcriptional modulation of interleukin-17A. Mol Cell Biol. 2011;31(17):3653–3669, with permission.

Figure 5

The Tnfsf11 gene locus and its osteoblastic and hematopoietic regulatory regions. Arrows indicate the CTCF/RAD21-defined boundaries of the locus that includes the transcription unit and its upstream non-coding regulatory control regions. Enhancers that mediate osteoblast lineage regulation (D regions) and hematopoietic regulation (T regions) are numbered and indicated in orange ovals. Their distance from the Tnfsf11 TSS in kb is indicated below the oval. The D5 enhancer is active in both cell lineage types. Factors that have been shown to bind to each enhancer by ChIP-chip and/or ChIP seq analysis are indicated below the gene locus in orange blocks.