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 D-3 [1,25(OH)(2)D-3] on skeletal and calcium homeostasis. In mice expressing the null mutation for 25-hydroxyvitamin D 1 alpha hydroxylase (1OHase(-/-)), or the vitamin D receptor (VDR-/-), 1,25(OH)(2)D-3 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)(2)D-3 and the VDR, and endogenous 1,25(OH)(2)D-3 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)(2)D-3 were each found to exert independent and complementary effects on skeletal anabolism, with PTH predominantly affecting appositional trabecular bone growth and 1,25(OH)(2)D-3 influencing both endochondral bone formation and appositional bone growth. Endooenous 1,25(OH)(2)D-3 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)(2)D-3 to double mutant PTH-/- IOHase(-/-) mice produced skeletal effects consistent with the actions of endogenous 1,25(OH)(2)D-3. These studies reveal an important skeletal anabolic role for both endogenous and exogenous 1.25(OH)(2)D-3 and point to a potential role for 1,25(OH)(2)D-3 analogs in the treatment of disorders of bone loss. (c) 2006 Elsevier Ltd. All rights reserved.