Cell Differentiation Proliferation and Apoptosis

Not only is calcitriol an important determinant for the differentiation of osteo-clastprecursor cells, it also directs the differentiation and maturation of normal and leukemic cells into monocytes, and potentiates apoptosis induced by 9-ds-retinoic acid, although it does not induce apoptosis itself. This suggests the possibility of what has been called maturation therapy for leukemia rather than conventional chemotherapy (James et al., 1999).

Calcitriol induces terminal differentiation of skin keratinocytes in culture, an action that has been exploited in the treatment of psoriasis (Section 3.6.2). In keratinocytes in culture, both calcium and calcitriol are required for differentiation. Cells lacking the calcium-sensing receptor or phospholipase C-y 1 fail to differentiate in response to calcium or calcitriol, suggesting that in addition to nuclear actions, calcitriol also modulates differentiation via cell surface receptors, phospholipase, and a protein kinase C cascade (Bikle et al., 2001; Bollinger and Bollag, 2001). Keratinocytes not only form cholecalciferol from 7-dehydrocholesterol (Section 3.2.1), but also hydroxylate it to calcitriol. This endogenous formation of calcitriol is regulated, and changes as the cells differentiate, so there is both endocrine and autocrine regulation of differentiation by calcitriol (Bikle, 1995).

Hair follicles also have calcitriol receptors and type II vitamin D-resistant rickets (Section 3.4.2), which is caused by lack of calcitriol receptor function, is associated with total alopecia, suggesting that calcitriol has a role in their development.

Vitamin D receptors have been identified in a variety of tumor cells. At low concentrations, calcitriol is a growth promoter, whereas at higher concentrations it inhibits proliferation of a variety of tumor cells in culture, including breast and prostate tumor cells. There is an epidemiological association between low vitamin D status and prostate cancer. Calcitriol has both antiproliferative andproapoptotic actions in cancer cells in culture. The antiproliferative effect is by suppression of growth stimulatory factors and the potentiation of growth inhibitory signals, and serves to introduce a block in the cell cycle at the transition from the G1 phase to the S phase. Apopotosis is induced by increased translocation of the proapoptotic Box protein into mitochondria, leading to increased formation of cytotoxic reactive oxygen species (Blutt and Weigel, 1999; Narvaez et al., 2001; Ylikomi et al., 2002).

Adipocytes have vitamin D receptors, and there is evidence that vitamin D may act as a suppressor of adipocyte development (Kawada et al., 1996). It has been suggested that vitamin D inadequacy may be a factor in the development of the metabolic syndrome ("syndrome X," the combination of insulin resistance, hyperlipidemia, and atherosclerosis associated with abdominal obesity). Sunlight exposure, and hence vitamin D status, may be a factor in the difference in incidence of atherosclerosis and myocardial infarction between northern and southern European countries; in addition to effects on adipocyte development, calcitriol also enhances insulin secretion through induction of calbindin-D (Section 3.3.7.1), and there is some evidence vitamin D supplements can improve glucose tolerance (Boucher, 1998).

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