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Increased formation and decreased resorption of bone in mice with elevated vitamin D receptor in mature cells of the osteoblastic lineage

EDITH M. GARDINER^*1, PAUL A. BALDOCK^*, GETHIN P. THOMAS^*, NATALIE A. SIMS^*,2, N. KATHRYN HENDERSON^*, BRUCE HOLLIS, CHRISTOPHER P. WHITE^*,3, KATHRYN L. SUNN^*, NIGEL A. MORRISON^*,4, WILLIAM R. WALSH and JOHN A. EISMAN^*

^* Bone and Mineral Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia;
Department of Pediatrics, Medical University of South Carolina, Charleston, South Carolina, USA; and
Department of Orthopaedics, Prince of Wales Hospital, Sydney, New South Wales

¹Correspondence: Garvan Institute of Medical Research, 384 Victoria St., Darlinghurst, Sydney, New South Wales 2010, Australia. E-mail e.gardiner{at}garvan.unsw.edu.au

The microarchitecture of bone is regulated by complex interactions between the bone-forming and resorbing cells, and several compounds regulate both actions. For example, vitamin D, which is required for bone mineralization, also stimulates bone resorption. Transgenic mice overexpressing the vitamin D receptor solely in mature cells of the osteoblastic bone-forming lineage were generated to test the potential therapeutic value of shifting the balance of vitamin D activity in favor of bone formation. Cortical bone was 5% wider and 15% stronger in these mice due to a doubling of periosteal mineral apposition rate without altered body weight or calcium homeostatic hormone levels. A 20% increase in trabecular bone volume in transgenic vertebrae was also observed, unexpectedly associated with a 30% reduction in resorption surface rather than greater bone formation. These findings indicate anabolic vitamin D activity in bone and identify a previously unknown pathway from mature osteoblastic cells to inhibit osteoclastic bone resorption, counterbalancing the known stimulatory action through immature osteoblastic cells. A therapeutic approach that both stimulates cortical anabolic and inhibits trabecular resorptive pathways would be ideal for treatment of osteoporosis and other osteopenic disorders.—Gardiner, E. M., Baldock, P. A., Thomas, G. P., Sims, N. A., Henderson, N. K., Hollis, B., White, C. P., Sunn, K. L., Morrison, N. A., Walsh, W. R., Eisman, J. A. Increased formation and decreased resorption of bone in mice with elevated vitamin D receptor in mature cells of the osteoblastic lineage.

Key Words: osteoclast • osteocyte • periosteum • uncoupling • turnover

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