Vitamin D and Human Health: Lessons from Vitamin D Receptor Null Mice
Roger Bouillon,
Geert Carmeliet,
Lieve Verlinden,
Evelyne van Etten,
Annemieke Verstuyf,
Hilary F. Luderer,
Liesbet Lieben,
Chantal Mathieu and
Marie 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{at}med.kuleuven.be
The vitamin D endocrine system is essential for calcium andbone homeostasis. The precise mode of action and the full spectrumof activities of the vitamin D hormone, 1,25-dihydroxyvitaminD [1,25-(OH)2D], can now be better evaluated by critical analysisof 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 phenotypethat mimics humans with the same congenital disease or severevitamin D deficiency. The intestine is the key target for theVDR because high calcium intake, or selective VDR rescue inthe 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 vitaminD endocrine system, suggesting a more widespread function. VDR-deficientmice, but not vitamin D- or 1-hydroxylase-deficient mice, andman develop total alopecia, indicating that the function ofthe VDR and its ligand is not fully overlapping. The immunesystem of VDR- or vitamin D-deficient mice is grossly normalbut shows increased sensitivity to autoimmune diseases suchas inflammatory bowel disease or type 1 diabetes after exposureto predisposing factors. VDR-deficient mice do not have a spontaneousincrease in cancer but are more prone to oncogene- or chemocarcinogen-inducedtumors. They also develop high renin hypertension, cardiac hypertrophy,and increased thrombogenicity. Vitamin D deficiency in humansis associated with increased prevalence of diseases, as predictedby the VDR null phenotype. Prospective vitamin D supplementationstudies with multiple noncalcemic endpoints are needed to definethe benefits of an optimal vitamin D status.
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