Use of genetically modified mice to examine the skeletal anabolic activity of vitamin D

We employed genetically modified mice to examine the role of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] on skeletal and calcium homeostasis. In mice expressing the null mutation for 25-hydroxyvitamin D 1α hydroxylase (1OHase−/−), or the vitamin D receptor (VDR−/−), 1,25(OH)2D3 and calcium were both required for optimal epiphyseal growth plate development, serum calcium and phosphorus alone were sufficient to mineralize skeletal tissue independent of 1,25(OH)2D3 and the VDR, and endogenous 1,25(OH)2D3 and the VDR were essential for baseline bone formation. In 2-week-old 1OHase−/− mice and in 2-week-old mice homozygous for the PTH null mutation(PTH−/−), PTH and 1,25(OH)2D3 were each found to exert independent and complementary effects on skeletal anabolism, with PTH predominantly affecting appositional trabecular bone growth and 1,25(OH)2D3 influencing both endochondral bone formation and appositional bone growth. Endogenous 1,25(OH)2D3 maintained serum calcium homeostasis predominantly by modifying intestinal and renal calcium transporters but not by producing net bone resorption. Administration of exogenous 1,25(OH)2D3 to double mutant PTH−/−1OHase−/− mice produced skeletal effects consistent with the actions of endogenous 1,25(OH)2D3. These studies reveal an important skeletal anabolic role for both endogenous and exogenous 1,25(OH)2D3 and point to a potential role for 1,25(OH)2D3 analogs in the treatment of disorders of bone loss.