Nonclassic actions of vitamin D

Abstract

Context: Vitamin D receptors are found in most tissues, not just those participating in the classic actions of vitamin D such as bone, gut, and kidney. These nonclassic tissues are therefore potential targets for the active metabolite of vitamin D, 1,25(OH)(2)D. Furthermore, many of these tissues also contain the enzyme CYP27B1 capable of producing 1,25(OH)(2)D from the circulating form of vitamin D. This review was intended to highlight the actions of 1,25(OH)(2)D in several of these tissues but starts with a review of vitamin D production, metabolism, and molecular mechanism.

Evidence acquisition: Medline was searched for articles describing actions of 1,25(OH)(2)D on parathyroid hormone and insulin secretion, immune responses, keratinocytes, and cancer.

Evidence synthesis: Vitamin D production in the skin provides an efficient source of vitamin D. Subsequent metabolism to 1,25(OH)(2)D within nonrenal tissues differs from that in the kidney. Although vitamin D receptor mediates the actions of 1,25(OH)(2)D, regulation of transcriptional activity is cell specific. 1,25(OH)(2)D inhibits PTH secretion but promotes insulin secretion, inhibits adaptive immunity but promotes innate immunity, and inhibits cell proliferation but stimulates their differentiation.

Conclusions: The nonclassic actions of vitamin D are cell specific and provide a number of potential new clinical applications for 1,25(OH)(2)D(3) and its analogs. However, the use of vitamin D metabolites and analogs for these applications remains limited by the classic actions of vitamin D leading to hypercalcemia and hypercalcuria.

Figure 1

Production of vitamin D₂ and vitamin D₃. Ergosterol in plants and 7-dehydrocholesterol in skin are the precursors for vitamin D₂ and vitamin D₃, respectively. UV light B breaks the B chain of each molecule to form the pre-D isomer, which then undergoes isomerization to D. D₂ and D₃ differ only in the side chain in which D₂ has a double bond between C22–C23 and a methyl group at C24. These differences alter somewhat its binding to DBP and metabolism.

Figure 2

Regulation of 1,25(OH)₂D production in the kidney. PTH stimulates and FGF23 inhibits 1,25(OH)₂D production in the kidney. In turn 1,25(OH)₂D inhibits PTH production and secretion from the parathyroid glands and stimulates FGF23 production from bone.

Figure 3

Regulation of immune function by 1,25(OH)₂D. 1,25(OH)₂D suppresses adaptive immunity (A) by inhibiting the maturation of dendritic cells, reducing their capacity to present antigen to CD4 cells. 1,25(OH)₂D further inhibits the proliferation and differentiation of CD4 cells into Th1 and Th17 cells and promotes the production of Th2 and Treg cells. On the other hand 1,25(OH)₂D promotes innate immunity (B) in that when the macrophage is activated by TLRs, VDR and CYP27B1 are induced enabling the macrophage to produce 1,25(OH)₂D, which then induces cathelicidin, a potent antimicrobial peptide.