The vitamin D endocrine system is essential for calcium and bone homeostasis. The precise mode of action and the full spectrum of activities of the vitamin D hormone, 1,25-dihydroxyvitamin D [1,25-(OH)(2)D], can now be better evaluated by critical analysis of mice with engineered deletion of the vitamin D receptor (VDR). Absence of a functional VDR or the key activating enzyme, 25-OHD-1alpha-hydroxylase (CYP27B1), in mice creates a bone and growth plate phenotype that mimics humans with the same congenital disease or severe vitamin D deficiency. The intestine is the key target for the VDR because high calcium intake, or selective VDR rescue in the intestine, restores a normal bone and growth plate phenotype. The VDR is nearly ubiquitously expressed, and almost all cells respond to 1,25-(OH)(2)D exposure; about 3% of the mouse or human genome is regulated, directly and/or indirectly, by the vitamin D endocrine system, suggesting a more widespread function. VDR-deficient mice, but not vitamin D- or 1alpha-hydroxylase-deficient mice, and man develop total alopecia, indicating that the function of the VDR and its ligand is not fully overlapping. The immune system of VDR- or vitamin D-deficient mice is grossly normal but shows increased sensitivity to autoimmune diseases such as inflammatory bowel disease or type 1 diabetes after exposure to predisposing factors. VDR-deficient mice do not have a spontaneous increase in cancer but are more prone to oncogene- or chemocarcinogen-induced tumors. They also develop high renin hypertension, cardiac hypertrophy, and increased thrombogenicity. Vitamin D deficiency in humans is associated with increased prevalence of diseases, as predicted by the VDR null phenotype. Prospective vitamin D supplementation studies with multiple noncalcemic endpoints are needed to define the benefits of an optimal vitamin D status.

, [1,25(OH) 2 D 3 ] is the hormonally active form of vitamin D. The genomic mechanism of 1,25(OH) 2 D 3 action involves the direct binding of the 1,25(OH) 2 D 3 activated vitamin D receptor/retinoic X receptor (VDR/RXR) heterodimeric complex to specific DNA sequences. Numerous VDR co-regulatory proteins have been identified, and genome-wide studies have shown that the actions of 1,25(OH) 2 D 3 involve regulation of gene activity at a range of locations many kilobases from the transcription start site. The structure of the liganded VDR/RXR complex was recently characterized using cryoelectron microscopy, X-ray scattering, and hydrogen deuterium exchange. These recent technological advances will result in a more complete understanding of VDR coactivator interactions, thus facilitating cell and gene specific clinical applications. Although the identification of mechanisms mediating VDR-regulated transcription has been one focus of recent research in the field, other topics of fundamental importance include the identification and functional significance of proteins involved in the metabolism of vitamin D. CYP2R1 has been identified as the most important 25-hydroxylase, and a critical role for CYP24A1 in humans was noted in studies showing that inactivating mutations in CYP24A1 are a probable cause of idiopathic infantile hypercalcemia. In addition, studies using knockout and transgenic mice have provided new insight on the physiological role of vitamin D in classical target tissues as well as evidence of extraskeletal effects of 1,25(OH) 2 D 3 including inhibition of cancer progression, effects on the cardiovascular system, and immunomodulatory effects in certain autoimmune diseases. Some of the mechanistic findings in mouse models have also been observed in humans. The identification of similar pathways in humans could lead to the development of new therapies to prevent and treat disease.

Metabolic switches in various immune cell subsets enforce phenotype and function. In the present study, we demonstrate that the active form of vitamin D, 1,25-dihydroxyvitamin D (1,25(OH)D), induces human monocyte-derived tolerogenic dendritic cells (DC) by metabolic reprogramming. Microarray analysis demonstrated that 1,25(OH)D upregulated several genes directly related to glucose metabolism, tricarboxylic acid cycle (TCA), and oxidative phosphorylation (OXPHOS). Although OXPHOS was promoted by 1,25(OH)D, hypoxia did not change the tolerogenic function of 1,25(OH)D-treated DCs. Instead, glucose availability and glycolysis, controlled by the PI3K/Akt/mTOR pathway, dictate the induction and maintenance of the 1,25(OH)D-conditioned tolerogenic DC phenotype and function. This metabolic reprogramming is unique for 1,25(OH)D, because the tolerogenic DC phenotype induced by other immune modulators did not depend on similar metabolic changes. We put forward that these metabolic insights in tolerogenic DC biology can be used to advance DC-based immunotherapies, influencing DC longevity and their resistance to environmental metabolic stress.

The secosteroid hormone 1alpha,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) is the natural ligand for the vitamin D receptor, a member of the nuclear receptor superfamily. Upon binding of the ligand, the vitamin D receptor heterodimerizes with the retinoid X receptor and binds to vitamin D response elements in the promoter region of target genes to induce/repress their expression. The target genes that have been identified so far are heterogeneous in nature and reflect the great spectrum of biological activities of 1,25(OH)(2)D(3). Within the last two decades, the receptor has been shown to be present not only in classical target tissues such as bone, kidney, and intestine, but also in many other nonclassical tissues, for example, in the immune system (T and B cells, macrophages, and monocytes), in the reproductive system (uterus, testis, ovary, prostate, placenta, and mammary glands), in the endocrine system (pancreas, pituitary, thyroid, and adrenal cortex), in muscles (skeletal, smooth, and heart muscles), and in brain, skin, and liver. Besides the almost universal presence of vitamin D receptors, different cell types (for example, keratinocytes, monocytes, bone, placenta) are capable of metabolizing 25-hydroxyvitamin D(3) to 1,25(OH)(2)D(3) by the enzyme 25(OH)D(3)-1alpha-hydroxylase, encoded by CYP27B1. The combined presence of CYP27B1 and the specific receptor in several tissues introduced the idea of a paracrine/autocrine role for 1,25(OH)(2)D(3). Moreover, it has been demonstrated that 1,25(OH)(2)D(3) can induce differentiation and inhibit proliferation of normal and malignant cells. Moreover, vitamin D deficiency is associated with an increased risk for nearly all major human diseases such as cancer, autoimmune diseases, cardiovascular, and metabolic diseases. In addition to the treatment of bone disorders with 1,25(OH)(2)D(3), these newly discovered functions open perspectives for the use of 1,25(OH)(2)D(3) as an immune modulator (for example, for the treatment of autoimmune diseases or prevention of graft rejection), inhibitor of cell proliferation, and inducer of cell differentiation (cancer).