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J. Biol. Chem., Vol. 279, Issue 16, 16754-16766, April 16, 2004

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Inactivation of the 25-Hydroxyvitamin D 1-Hydroxylase and Vitamin D Receptor Demonstrates Independent and Interdependent Effects of Calcium and Vitamin D on Skeletal and Mineral Homeostasis^*

Dibyendu K. Panda, Dengshun Miao, Isabel Bolivar, Jiarong Li, Rujuan Huo, Geoffrey N. Hendy, and David Goltzman

From the Calcium Research Laboratory, Departments of Medicine, Physiology, and Human Genetics, McGill University Health Centre and McGill University, Montreal, Quebec H3A 1A1, Canada

We employed a genetic approach to determine whether deficiency of 1,25-dihydroxyvitamin D (1,25(OH)₂D) and deficiency of the vitamin D receptor (VDR) produce the same alterations in skeletal and calcium homeostasis and whether calcium can subserve the skeletal functions of 1,25(OH)₂D and the VDR. Mice with targeted deletion of the 25-hydroxyvitamin D 1-hydroxylase (1(OH)ase^-/-) gene, the VDR gene, and both genes were exposed to 1) a high calcium intake, which maintained fertility but left mice hypocalcemic; 2) this intake plus three times weekly injections of 1,25(OH)₂D₃, which normalized calcium in the 1(OH)ase^-/- mice only; or 3) a "rescue" diet, which normalized calcium in all mutants. These regimens induced different phenotypic changes, thereby disclosing selective modulation by calcium and the vitamin D system. Parathyroid gland size and the development of the cartilaginous growth plate were each regulated by calcium and by 1,25(OH)₂D₃ but independent of the VDR. Parathyroid hormone secretion and mineralization of bone reflected ambient calcium levels rather than the 1,25(OH)₂D/VDR system. In contrast, increased calcium absorption and optimal osteoblastogenesis and osteoclastogenesis were modulated by the 1,25(OH)₂D/VDR system. These studies indicate that the calcium ion and the 1,25(OH)₂D/VDR system exert discrete effects on skeletal and calcium homeostasis, which may occur coordinately or independently.

Received for publication, September 16, 2003 , and in revised form, January 6, 2004.

^* This work was supported by Canadian Institutes of Health Research Grants IMH-63263 (to D. M.), MOP-57730 (to G. N. H.), and MOP-5775 (to D. G.), a grant from the Kidney Foundation of Canada (to G. N. H.), and National Cancer Institute of Canada Grant 012243 (to D. G.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

These two authors contributed equally to this work.

To whom correspondence should be addressed: Calcium Research Laboratory, Dept. of Medicine, Royal Victoria Hospital, H4.67, 687 Pine Ave. W., Montreal, Quebec H3A 1A1, Canada. Tel.: 514-843-1632; Fax: 514-843-1712; E-mail: david.goltzman{at}mcgill.ca.

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