Vitamin D and human health: lessons from vitamin D receptor null mice.

Abstract

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)(2)D], 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-1alpha-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)(2)D 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 1alpha-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.

• Authors: Roger Bouillon, Geert Carmeliet, Lieve Verlinden, Evelyne van Etten, Annemieke Verstuyf, Hilary F Luderer, Liesbet Lieben, Chantal Mathieu, Marie Demay
• Journal: Endocrine reviews (Endocr Rev) Vol. 29 Issue 6 Pg. 726-76 (Oct 2008) ISSN: 0163-769X [Print] United States
• PMID: 18694980 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Review)

Chemical References

• Receptors, Calcitriol
• Vitamin D

Topics

• Animals
• Disease Models, Animal
• Endocrine System (physiology)
• Endocrine System Diseases (physiopathology)
• Humans
• Mice
• Mice, Knockout
• Receptors, Calcitriol (genetics, physiology)
• Vitamin D (physiology)