Bioactive vitamin D or calcitriol is a steroid hormone that has long been known for its important role in regulating body levels of calcium and phosphorus, and in mineralization of bone. More recently, it has become clear that receptors for vitamin D are present in a wide variety of cells, and that this hormone has biologic effects which extend far beyond control of mineral metabolism. Vitamin D is thus not a true vitamin, as it can be synthesized in adequate amounts by most mammals exposed to sunlight (cats and dogs cannot synthesize vitamin D and must receive it in their diet). An organic chemical compound (or related set of compounds) is only scientifically called a vitamin when it cannot be synthesized in sufficient quantities by an organism, and must be obtained from their diet. However, as with other compounds commonly called vitamins, vitamin D was discovered in an effort to find the dietry substance that was lacking in a disease, namely, rickets, the childhood form of osteomalacia.
ROLE OF VITAMIN D IN REGULATION OF SEVERAL GENES:
The vitamin D hormones have essential roles in human health. Vitamin D hormones act by binding to and activating the vitamin D receptor (VDR) to regulate the expression of genes in a tissue-specific manner. Vitamin D hormones regulate blood calcium levels by controlling intestinal absorption of dietary calcium and reabsorption of calcium by the kidneys. Concomitantly, vitamin D hormones also suppress the production of the calcium regulating hormone, parathyroid hormone (PTH), which is produced by the parathyroid glands. The vitamin D hormones also participate in the regulation of cellular differentiation and growth, as well as bone formation and metabolism.
Additionally, vitamin D hormones are required for the normal functioning of the musculoskeletal, immune and renin-angiotensin systems. There is a growing body of evidence linking vitamin D insufficiency with cognitive and neural dysfunction. The widespread beneficial effects of vitamin D hormones are continually being elucidated through studies directed to the intracellular VDR and the corresponding networks of VDR-responsive genes in nearly every human tissue. It is becoming evident that vitamin D insufficiency has a widespread and significant impact on a number of key physiological systems.
METABOLISM OF VITAMIN D:
Both forms of vitamin D undergo identical metabolism . Some evidence indicates that vitamin D2 may be metabolized more rapidly than vitamin D3, but with regular daily intake they can be considered bioequivalent. Both forms of vitamin D are converted to 25-hydroxyvitamin [25(OH)D] in the liver, and the serum level of 25(OH) D is measured to determine the adequacy of vitamin D status. In the kidney, 25(OH)D is hydroxylated to 1, 25-dihydroxyvitamin D [1, 25(OH)2 D], which is the only biologically active form of vitamin D. Acting principally on the duodenum, 1, 25(OH)2 D increases calcium absorption. It also acts on bone cells, both osteoblasts and osteoclasts, to mobilize calcium. The synthesis of 1, 25(OH)2 D is tightly regulated and stimulated primarily by serum parathyroid hormone
THE VITAMIN D RECEPTER AND MECHANISM OF ACTION:
The vitamin D system is unique in that distinct calcium homeostatic functions and cell growth regulatory activities are mediated through a single ligand, calcitriol, acting through a specific receptor exhibiting ubiquitous tissue expression, the vitamin D receptor (VDR). The VDR is a member of a superfamily of nuclear steroid hormone receptors which regulate gene transcription by interacting with response elements in gene promoters. Structure-function analysis of the VDR protein has defined distinct domains involved in DNA binding, ligand binding, receptor dimerisation and gene transactivation, including a C-terminal activation function domain (AF-2) that is important for cofactor interaction.
A model for regulation of gene transcription by the VDR is evolving and proposes VDR interaction with various components of the basal transcriptional machinery, including newly defined coactivators and corepressors, which may act to regulate gene transcription by altering histone acetylation and chromatin structure. This review describes the vitamin D endocrine system and the role of the VDR in regulating this system, including the molecular basis for the diverse actions of synthetic calcitriol analogues in the treatment of autoimmune disease and cancer.
ROLE OF VITAMIN D AS HORMONE
Vitamin D and Bone Cell Activity:
Approximately 60 genes are known to respond to vitamin D. Many of these vitamin D responsive genes are expressed by the bone forming cells (osteoblasts) which include:
* type I collagen.
* alkaline phosphatase,
* tumour necrosis factor ligand member (RANKL)
Tumour necrosis factor ligand member (RANKL) is central to osteoclastogenesis. The bone resorbing cells (osteoclasts) also express vitamin D-responsive genes. It is evident that 1,25(OH)2D plays a major role in controlling osteoclastogenesis and bone resorption through its modulation of the RANKL gene in osteoblasts.
These types of results are increasing interest in the view that the modulation of vitamin D activity within bone cells, either through the vitamin D receptor or metabolism of vitamin D, has effects on the levels of bone mineral. It is through such a mechanism that higher levels of vitamin D in the elderly may provide protection against hip fractures.
Cancer prevention: Role of vitamin D in prostate cancer:
Prostate cancer is the second leading cause of cancer deaths in men in the United States. Developing new treatment strategies is critical to improving the health of men. Our research has focused on four areas in which we have pursued the possible use of 1alpha,25(OH)(2)D(3) and its analogs to treat prostate cancer.The results of a clinical trial of 1alpha,25(OH)(2)D(3) treatment of patients with early recurrent prostate cancer. We provide preliminary evidence that 1alpha,25(OH)(2)D(3) may be effective in slowing the rate of PSA rise in selected cases of prostate cancer. In conclusion, we believe that 1alpha,25(OH)(2)D(3) has a role in thetreatment and/or prevention strategies being developed for prostate cancer. However, to increase antiproliferative potency without increasing side-effects, the use of less calcemic analogs appears to be the most reasonable approach.
Role of vitamin D in breast cancer:
In addition to its role in calcium homeostasis and bone health, vitamin D has also been reported to have anticancer activities against many cancer types, including breast cancer. The discovery that breast epithelial cells possess the same enzymatic system as the kidney, allowing local manufacture of active vitamin D from circulating precursors, makes the effect of vitamin D in breast cancer biologically plausible. Preclinical and ecologic studies have suggested a role for vitamin D in breast cancer prevention. Inverse associations have also been shown between serum 25-hydroxyvitamin D level (25(OH)D) and breast cancer development, risk for breast cancer recurrence, and mortality in women with early-stage breast cancer. Clinical trials of vitamin D supplementation, however, have yielded inconsistent results.
Regardless of whether or not vitamin D helps prevent breast cancer or its recurrence, vitamin D deficiency in the U.S. population is very common, and the adverse impact on bone health, a particular concern for breast cancer survivors, makes it important to understand vitamin D physiology and to recognize and treat vitamin D deficiency. In this review, we discuss vitamin D metabolism and its mechanism of action. We summarize the current evidence of the relationship between vitamin D and breast cancer, highlight ongoing research in this area, and discuss optimal dosing of vitamin D for breast cancer prevention.
Role of vitamin D in auto immune diseases:
Vitamin D and its prohormones have been the focus of a growing number of studies in past years, demonstrating their function not only in calcium metabolism and bone formation, but also their interaction with the immune system, which is not surprising, since vitamin D receptors are expressed in different tissues, such as brain, heart, skin, bowel, gonads, prostate, breasts, and immune cells, as well as bones, kidneys, and parathyroid glands.Current studies have related vitamin D deficiency with several autoimmune disorders, including insulindependent diabetes mellitus (IDDM), multiple sclerosis (MS), inflammatory bowel disease (IBD), systemic lupus erythematosus (SLE), and rheumatoid arthritis (RA). In view of those associations, it has been suggested that vitamin D is an extrinsic factor capable of affecting the prevalence of autoimmune diseases.
Vitamin D seems to interact with the immune system through its actions on the regulation and differentiation of cells like lymphocytes, macrophages, and natural killer cells (NK), besides interfering in the in vivo and in vitro production of cytokines. Among the immunomodulatory effects demonstrated we should mention: a reduction in the production of interleukin-2 (IL-2), gamma interferon (INFÎ³), and tumor necrosis factor (TNF); inhibition of the expression of IL-6; and inhibition of the secretion and production of autoantibodies by B lymphocytes.
Vitamin D modulation of immune responses:
Dendritic cells (DCs) are primary targets for the immunomodulatory activity of 1, 25(OH)2D3, as indicated by inhibited DC differentiation and maturation, leading to downregulated expression of MHC-II, costimulatory molecules (CD40, CD80 and CD86) and decreased production of IL-12. Moreover, 1, 25(OH)2D3 enhances IL-10 production and promotes DC apoptosis. Together, these effects of 1, 25(OH)2D3 inhibit DC-dependent T-cell activation. In particular, the active synthesis of 1, 25(OH)2D3 seems to exert an autoregulatory function by inhibiting the differentiation of monocyte precursors into immature DCs and the subsequent ability of the immature DCs to undergo terminal differentiation in response to maturation stimuli.
FIG. Mechanisms involved in vitamin D modulation of the immune responses. DCs are primary targetsfor the immunomodulatory activity of 1, 25(OH)2D3, as indicated by inhibited DC differentiation and maturation, together with inhibition of differentiation of monocyte precursors into immature DCs. 1, 25(OH)2D3 suppresses Th1 (and Th17)driven cytokine responses, induces Treg cells, induces IL-4 production (Th2) and enhances NKTcell function. Differentiation and maturation of B cells is also inhibited. Th are CD4+ helper cell subsets (Th1, Th2, Th3-Treg, Th17) originating from naÄ±ve T cell (Th0). Thin arrows (left) indicate cytokines that induce differentiation of Th0 cells and thicker arrows (right) indicate cytokines produced by activated Th cell subsets. All T cells that have been tested express the VDR. B cells and NKT cells are also reported.The yellow circles indicate the cytokines/activities inhibited by vitamin D.On the contrary, the green circles indicate the cytokines enhanced by vitaminD.
Knowledge of the physiology and pathology of vitamin D is currently increasing at a rapid rate. The realisation that vitamin D can act in a paracrine and autocrine manner in addition to its well-described endocrine action opens up considerable opportunities for the development of new understanding of the requirement for an adequate vitamin D status for optimal health. It is encouraging that the relatively simple and cheap practice of maintaining an adequate vitamin D status has the potential to provide health benefits in a number of areas, which afflict an increasing proportion of the population, as well as consume an increasing proportion of the healthcare budget to provide treatment. The reduction of the risk of hip fracture in the elderly is one such area.
A high priority of research must be to identify the critical 25OHD values required to maintain a healthy skeleton in the elderly. As well research must determine whether a low vitamin D status influences the development of cancer, whether it increases the absolute risk of cancer or whether it modulates the growth or invasiveness of cancers. Clinical laboratory professionals have a responsibility to improve the precision and accuracy of current 25OHD assays in clinical use. This work will require the collaboration between the profession and instrument and reagent manufacturers. The International Federation of Clinical Chemistry and Laboratory Medicine is in an optimal position to coordinate such a project.