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Exogenous 1,25-Dihydroxyvitamin D₃ Exerts a Skeletal Anabolic Effect and Improves Mineral Ion Homeostasis in Mice that Are Homozygous for Both the 1-Hydroxylase and Parathyroid Hormone Null Alleles

The Research Center for Bone and Stem Cells (Y.X., D.M.), Department of Anatomy, Histology, and Embryology and Institute of Dental Research, Nanjing Medical University, Nanjing, Jiangsu, People’s Republic of China; Calcium Research Laboratory (Y.X., G.N.H., D.G., D.M.), McGill University Health Centre, and Department of Medicine, McGill University, Montréal, Québec H3A 1A1, Canada; and Lady Davis Research Institute (A.C.K.), Sir Mortimer B. Davis-Jewish General Hospital and Department of Medicine, McGill University, Montréal, Québec H3T 1E2, Canada

Address all correspondence and requests for reprints to: Dr. Dengshun Miao, The Research Center for Bone and Stem Cells, Department of Anatomy, Histology, and Embryology and Institute of Dental Research, Nanjing Medical University, Nanjing, Jiangsu 210029, The People’s Republic of China. E-mail: dsmiao{at}njmu.edu.cn.

1,25-Dihydroxyvitamin D₃ [1,25(OH)₂D₃] and PTH each modulate calcium and skeletal homeostasis. To identify 1,25(OH)₂D₃-mediated skeletal and mineral ion actions independent of PTH, double-knockout mice, which are homozygous for both the 1-hydroxylase and PTH null alleles, were treated with 1,25(OH)₂D₃, sc, from d 4 to 14 and compared with vehicle-treated animals. Serum calcium rose in 1,25(OH)₂D₃-treated double-knockout mice, and messenger RNA and protein levels of the renal calcium transporters TRPV5, calbindin-D_28K, calbindin-D_9K, and Na⁺/Ca²⁺ exchanger 1 were up-regulated. Parameters of endochondral bone formation, including long bone length, epiphyseal volume, chondrocyte proliferation and differentiation, and cartilage matrix mineralization, were all increased by 1,25(OH)₂D₃, Exogenous 1,25(OH)₂D₃ also increased both trabecular and cortical bone; augmented both osteoblast number and type I collagen deposition in bone matrix; and up-regulated expression levels of the osteoblastic genes alkaline phosphatase, type I collagen, and osteocalcin. Furthermore, in 1,25(OH)₂D₃-treated double mutants, osteoclastic bone resorption appeared to decline. The results indicate that administered 1,25(OH)₂D₃ used intestinal and renal but not skeletal mechanisms to elevate serum calcium and that this sterol can promote endochondral and appositional bone increases independent of endogenous PTH.

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