Vitamin D action : Lessons learned from genetic mouse models

Mouse models with targeted deletion of the genes encoding the enzyme 25-hydroxyvitamin D 1alpha-hydroxylase [1alpha(OH)ase], and the vitamin D receptor (VDR), have provided considerable insight into the regulation of mineral and skeletal physiology by 1,25-dihydroxyvitamin D [1,25(OH)(2)D]. Dietary manipulation induced different phenotypic changes and demonstrated that parathyroid gland function is coordinately regulated by calcium and 1,25(OH)(2)D, but that mineralization of bone reflects ambient calcium (and phosphorus) levels rather than direct actions of the 1,25(OH)(2)D/VDR system. In contrast, increased calcium absorption and optimal osteoblastogenesis and bone formation is modulated by the 1,25(OH)(2)D/VDR system. Similar models have also been employed to study extraskeletal vitamin D actions. For example, increased blood pressure, activation of the renin/angiotensin system, myocardial hypertrophy, and cardiac dysfunction were observed in 1alphaOHase(-/-) mice, and could be prevented by 1,25(OH)(2)D(3) administration. These models allow controlled examination of the pathophysiology associated with1,25(OH)(2)D deficiency and intervention to prevent and treat these disorders.