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This version published online on July 20, 2006
Endocrinology, doi:10.1210/en.2006-0403
A more recent version of this article appeared on October 1, 2006
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Submitted on March 30, 2006
Accepted on July 10, 2006

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

Yingben Xue, Andrew C. Karaplis, Geoffrey N. Hendy, David Goltzman, and 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, P.R. of China; Calcium Research Laboratory, McGill University Health Centre and Department of Medicine, McGill University, Montreal, Quebec H3A 1A1, Canada and Lady Davis Research Institute, Sir Mortimer B. Davis - Jewish General Hospital and Department of Medicine McGill University, Montreal, Quebec H3T 1E2, Canada

* To whom correspondence should be addressed. E-mail: dsmiao{at}njmu.edu.cn.

1,25-Dihydroxyvitamin D3 (1,25(OH)2D3) and parathyroid hormone (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{alpha}-hydroxylase and PTH null alleles were treated with 1,25(OH)2D3, subcutaneously, from day 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-D28K, calbindin-D9K and NCX1 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 employed 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.
Key words: 1,25-Dihydroxyvitamin D3 • skeletal anabolism • ion homeostasis • 1-{alpha} Hydroxylase • parathyroid hormone






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