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Vitamin D and Human Health: Lessons from Vitamin D Receptor Null Mice

Katholieke Universiteit Leuven, Laboratory of Experimental Medicine and Endocrinology (R.B., G.C., L.V., E.v.E., A.V., L.L., C.M.), 3000 Leuven, Belgium; and Massachusetts General Hospital, Endocrine Unit (H.F.L., M.D.), Boston Massachusetts 02114

Correspondence: Address all correspondence and requests for reprints to: Roger Bouillon, Katholieke Universiteit Leuven, Laboratory of Experimental Medicine and Endocrinology, Herestraat 49, O&N 1 bus 902, 3000 Leuven, Belgium. E-mail: Roger.Bouillon{at}med.kuleuven.be

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)₂D], 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-1-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)₂D 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 1-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.

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