25-Hydroxyvitamin D-1α Hydroxylase: Studies in Mouse Models and Implications for Human Disease

Genetic mouse models with targeted deletion (“knockout”) of the 25-hydroxyvitamin D-1alpha-hydroxylase gene 1α(OH)ase^−/−], as well as with targeted deletion of the VDR gene, when exposed to different dietary regimens, have provided considerable insight into the molecular regulation of skeletal physiology by the 1,25(OH)₂D/VDR system. These regimens induced different phenotypic changes and demonstrated that parathyroid gland size and the development of the cartilaginous growth plate were each co-ordinately regulated by calcium and by 1,25(OH)₂D, and that parathyroid hormone (PTH) secretion and mineralization of bone reflected ambient calcium (and phosphorus) levels rather than the direct actions of the 1,25(OH)₂D/VDR system. In contrast, increased calcium absorption, optimal osteoblastogenesis, and baseline bone formation were observed to be modulated by 1,25(OH)₂D/VDR signaling. These bone anabolic effects of endogenous 1,25(OH)₂D were evident in neonatal mice as well as in older animals, and exogenous 1,25(OH)₂D₃ was also found to stimulate trabecular and cortical bone formation in neonatal double homozygous 1α(OH)ase^−/−PTH^−/− mice. Furthermore, the anabolic effect of exogenously administered PTH appeared to be partly dependent on the stimulation of endogenous 1,25(OH)₂D. Genetic mouse models have also been employed to study extra-skeletal actions modulated by the 1,25(OH)₂D/VDR system. For example, increased blood pressure, activation of the renin/angiotensin system, myocardial hypertrophy, and cardiac dysfunction were observed in 1αOHase^−/− mice, and these alterations could be prevented by treatment with 1,25(OH)₂D₃. These models allow controlled examination of the regulation of both skeletal and extra-skeletal pathophysiology associated with 1,25(OH)₂D deficiency which appear to be relevant to humans, and facilitate studies to prevent and treat these disorders by active vitamin D forms.