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Molecular Endocrinology, doi:10.1210/me.2003-0498
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Molecular Endocrinology 18 (5): 1222-1237
Copyright © 2004 by The Endocrine Society

The Wnt Antagonist Secreted Frizzled-Related Protein-1 Is a Negative Regulator of Trabecular Bone Formation in Adult Mice

Peter V. N. Bodine, Weiguang Zhao, Yogendra P. Kharode, Frederick J. Bex, Andre-Jean Lambert, Mary Beth Goad, Tripti Gaur, Gary S. Stein, Jane B. Lian and Barry S. Komm

Women’s Heath Research Institute (P.V.N.B., Y.P.K., F.J.B., B.S.K.), Wyeth Research, Collegeville, Pennsylvania 19426; Aventis Pharmaceuticals (W.Z.), Bridgewater, New Jersey 08807; Pathology (A.-J.L.), Wyeth Research, Chazy, New York 12921; Investigational Pathology (M.B.G.), Wyeth Research, Andover, Massachusetts 01818; and Department of Cell Biology (T.G., G.S.S., J.B.L.), University of Massachusetts Medical School, Worcester, Massachusetts 01655

Address all correspondence and requests for reprints to: Dr. Peter V. N. Bodine, Women’s Health Research Institute, Wyeth Research, 500 Arcola Road, Collegeville, Pennsylvania 19426. E-mail: bodinep{at}wyeth.com.

Previous studies have associated activation of canonical Wnt signaling in osteoblasts with elevated bone formation. Here we report that deletion of the murine Wnt antagonist, secreted frizzled-related protein (sFRP)-1, prolongs and enhances trabecular bone accrual in adult animals. sFRP-1 mRNA was expressed in bones and other tissues of +/+ mice but was not observed in –/– animals. Despite its broad tissue distribution, ablation of sFRP-1 did not affect blood and urine chemistries, most nonskeletal organs, or cortical bone. However, sFRP-1–/– mice exhibited increased trabecular bone mineral density, volume, and mineral apposition rate when compared with +/+ controls. The heightened trabecular bone mass of sFRP-1–/– mice was observed in adult animals between the ages of 13–52 wk, occurred in multiple skeletal sites, and was seen in both sexes. Mechanistically, loss of sFRP-1 reduced osteoblast and osteocyte apoptosis in vivo. In addition, deletion of sFRP-1 inhibited osteoblast lineage cell apoptosis while enhancing the proliferation and differentiation of these cells in vitro. Ablation of sFRP-1 also increased osteoclastogenesis in vitro, although changes in bone resorption were not observed in intact animals in vivo. Our findings demonstrate that deletion of sFRP-1 preferentially activates Wnt signaling in osteoblasts, leading to enhanced trabecular bone formation in adults.




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