Extraskeletal actions of vitamin D

Abstract

The vitamin D receptor (VDR) is found in nearly all, if not all, cells in the body. The enzyme that produces the active metabolite of vitamin D and ligand for VDR, namely CYP27B1, likewise is widely expressed in many cells of the body. These observations indicate that the role of vitamin D is not limited to regulation of bone and mineral homeostasis, as important as that is. Rather, the study of its extraskeletal actions has become the major driving force behind the significant increase in research articles on vitamin D published over the past several decades. A great deal of information has accumulated from cell culture studies, in vivo animal studies, and clinical association studies that confirms that extraskeletal effects of vitamin D are truly widespread and substantial. However, randomized, placebo-controlled clinical trials, when done, have by and large not produced the benefits anticipated by the in vitro cell culture and in vivo animal studies. In this review, I will examine the role of vitamin D signaling in a number of extraskeletal tissues and assess the success of translating these findings into treatments of human diseases affecting those extracellular tissues.

Keywords: CYP27B1; cancer; cardiovascular; immune system; skin; vitamin D.

Figure 1

Mechanisms by which 1,25(OH)2D suppresses cancer formation.

Figure 2

Regulation of cardiovascular function. 1,25(OH)2D inhibits the production of renin by both the kidney and heart as well as ANF by the heart. Renin in turn catalyzes the production of angiotensin, a powerful vasculoconstrictor as well as stimulator of aldosterone production, that results in hypertension.

Figure 3

Regulation of insulin secretion and peripheral action. 1,25(OH)2D along with calcium promotes the secretion of insulin and its stimulation of gluose uptake by peripheral tissues. Insulin in turn promotes the production of 1,25(OH)2D by the kidney.

Figure 4

Sequential regulation of epidermal differentiation by 1,25(OH)2D–VDR and its coactivators. The DRIP (Mediator) complex is located primarily in stratum basale/spinosum and modulates 1,25(OH)2D–VDR regulation of proliferation, hair follicle cycling, and the early stages of differentiation, whereas SRC2/3 complexes are preferentially expressed in the upper layers of the epidermis where they modulate 1,25(OH)2D/VDR regulation of barrier function and innate immunity.

Figure 5

The rapid actions of 1,25(OH)2D–VDR on calcium flux within the muscle cell. VDR is translocated from the nucleus to the membrane where it is activated by 1,25(OH)2D to stimulate calcium influx through store operated (SOC) and voltage dependent (VDCC) calcium channels. 1,25(OH)2D–VDR also activates phospholipase C γ (PLCγ) that in turn hydrolyzes phosphatidylinositol bisphosphate (PIP2) to inositol trisphosphate (IP3) and diacyl glycerol (DG). IP3 stimulates the release of calcium from the sarcoplasmic reticulum; DG activates protein kinase C. 1,25(OH)2D/VDR also activates adenyl cyclase (AC), producing cAMP, and activates the mitogen activated protein kinase (MAPK) pathway (not shown).

Figure 6

Regulation of the adaptive and innate immune pathways. (A) Adaptive immunity. 1,25(OH)2D, which is produced by dendritic cells, decreases the maturation and antigen presenting ability of dendritic cells and alters the profile of T helper cells that differentiate from the activated CD4 parent cell. In particular, 1,25(OH)2D reduces the formation of Th1, Th17, and Th9 cells, while promoting the differentiation of Th2 and Treg cells. The result is overall suppression of the adaptive immune pathway. (B) Innate immunity. Activation of selective Toll-like receptors (TLR1/2) by products of infectious organisms such as the lipopeptides from M. tuberculosis results in the induction of both the VDR and CYP27B1. In the presence of adequate substrate (25OHD), 1,25(OH)2D is produced that, in combination with the VDR, induces the formation of antimicrobial peptides such as cathelicidin, whichi are capable of killing intracellular organisms like M. tuberculosis.

Figure 6

Regulation of the adaptive and innate immune pathways. (A) Adaptive immunity. 1,25(OH)2D, which is produced by dendritic cells, decreases the maturation and antigen presenting ability of dendritic cells and alters the profile of T helper cells that differentiate from the activated CD4 parent cell. In particular, 1,25(OH)2D reduces the formation of Th1, Th17, and Th9 cells, while promoting the differentiation of Th2 and Treg cells. The result is overall suppression of the adaptive immune pathway. (B) Innate immunity. Activation of selective Toll-like receptors (TLR1/2) by products of infectious organisms such as the lipopeptides from M. tuberculosis results in the induction of both the VDR and CYP27B1. In the presence of adequate substrate (25OHD), 1,25(OH)2D is produced that, in combination with the VDR, induces the formation of antimicrobial peptides such as cathelicidin, whichi are capable of killing intracellular organisms like M. tuberculosis.