Endocrine Abstracts (2006) 11 S8

Vitamin D action

R Bouillon

Katholieke Universiteit Leuven, Leuven, Belgium.

Ligand activated VDR regulates about 3% the mouse genome. Its classical function is to regulate calcium and bone homeostasis. 1,25-(OH)2D is essential for transepithelial calcium transport in the intestine (by an epithelial calcium channel, TRPV6) and in the kidney (TRPV5). Normal osteoclastogenesis and bone resorption as well as bone mineralisation is possible in the absence of VDR when VDR KO men or animals receive a high calcium diet. VDR.1α,25-(OH)2D3 also have major effects on many other non-classical target tissues as demonstrated in VDR KO mice and men (keratinocytes and hair follicles: alopecia; high renin hypertension; muscle cell maturation defect; differentiation of dendritic/immune cells). Finally all VDR positive cells react to VDR.1,25-(OH)2D by inhibition of proliferation regulated by a coherent action on cell cycle genes.

Vitamin D deficiency rickets was rapidly eradicated by widespread vitamin D supplementation. Vitamin D deficiency is still widespread in the elderly population and contributes to osteoporotic fractures. Animal studies support human epidemiological data of a possible link between poor vitamin D status and autoimmune diseases (type 1 diabetes, MS, IBD) and major cancers (breast, prostate, colon cancer). The optimal vitamin D status is not well defined but levels <10 ng/ml are certainly deficient, 25 OHD above 20 ng/ml are desirable for optimal bone health. Whether higher levels would be beneficial for general health will requires large scale intervention studies. Out of more than 3000 synthetic analogues of vitamin D some show selective receptor modulating activity (antiproliferative or immune modulator effects or alternatively by anti-osteoporotic effects, with minimal calcemic activity).

The mode of action of superagonistic and/or selective activation of VDR is not completely understood but involves extra– and intracellular pharmacokinetics, VDR stability and above all selective recruitment of coactivators.

Clinical use of vitamin D analogues is presently limited but likely to expand rapidly.

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