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 1alpha 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. Endogenous 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(-/-)1OHase(-/-) 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.
Goltzman
David
D
Department of Medicine and Calcium Research Laboratory, McGill University Health Centre and McGill University, 687 Pine Avenue West, Room H4.67, Montreal, Quebec, Canada H3A 1A1. david.goltzman@mcgill.ca
D000375:Aging / Q000502:physiology; D000818:Animals; D000831:Animals, Newborn; D001842:Bone and Bones / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D014807:Vitamin D / Q000378:metabolism*
D014807:Vitamin D