The noncalciotropic actions of vitamin D: recent clinical developments

Abstract

Purpose of review: This review summarizes recently described actions of 1,25-dihydroxyvitamin D beyond its function in calcium homeostasis and bone metabolism.

Recent findings: 1,25-Dihydroxyvitamin D stimulates the innate immune system, facilitating the clearance of infections such as tuberculosis. Hypovitaminosis D has been associated with several autoimmune disorders, various malignancies, and cardiovascular risk factors in a number of recent epidemiologic reports. Based on these observational reports, vitamin D and its analogues are being evaluated for the prevention and treatment of a variety of conditions, with early findings showing mixed results.

Summary: The broad tissue distribution of the 25-hydroxyvitamin D 1alpha-hydroxylase enzyme and the vitamin D receptor establish a role for 1,25-dihydroxyvitamin D in the pathophysiology of various disease states and provide new therapeutic targets for vitamin D and its analogues.

Figures

Figure 1. Vitamin D Metabolism and Actions

The calciotropic functions of 1,25-(OH)2-D include the physiological regulation of calcium transport and bone mineralization. The synthesis of circulating 1,25-(OH)2-D which mediates these calciotropic actions is tightly regulated. Non-calciotropic actions involve the activation of vitamin D receptors (VDRs) by locally produced 1,25-(OH)2-D in a number of tissues in a paracrine and autocrine fashion.

Figure 2. Vitamin D and the Immune Response to Mycobacterium Tuberculosis

Activation of the Toll-Like Receptor 2/1 (TLR 2/1) heterodimer by Mycobacterium tuberculosis(A) upregulates the expression of 1α-hydroxylase and VDR genes in monocytes and macrophages (B). In the presence of sufficient 25-OH-D, this upregulation leads to a 1,25-(OH)2-D–dependent induction of the antimicrobial peptide cathelicidin (C) and enhanced killing of intracellular M. tuberculosis(D). In a granuloma, surrounding T-helper 1 (TH1) cells produce γ-interferon (INFγ) which further enhances 1α-hydroxylase expression (E). Excess 1,25-(OH)2-D inhibits the differentiation of undifferentiated T-helper cells (TH0) to TH1 cells in a paracrine fashion (E), providing a mechanism to prevent excessive 1,25-(OH)2-D production.