Endocrine Reviews 29 (6): 726-776
Copyright © 2008 by The Endocrine Society
Vitamin D and Human Health: Lessons from Vitamin D Receptor Null MiceRoger Bouillon, Geert Carmeliet,Lieve Verlinden, Evelyne van Etten,Annemieke Verstuyf, Hilary F. Luderer,Liesbet Lieben, Chantal Mathieu andMarie Demay 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@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 theVDR 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 cellsrespond to 1,25-(OH)2D exposure; about 3% of the mouse or humangenome 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.
