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J. Biol. Chem., Vol. 281, Issue 42, 31720-31728, October 20, 2006

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Wnt/-Catenin Signaling Is a Normal Physiological Response to Mechanical Loading in Bone^*

John A. Robinson²¹, Moitreyee Chatterjee-Kishore², Paul J. Yaworsky, Diane M. Cullen^¶, Weiguang Zhao³, Christine Li, Yogendra Kharode, Linda Sauter⁴, Philip Babij⁵, Eugene L. Brown, Andrew A. Hill, Mohammed P. Akhter^¶, Mark L. Johnson^¶6, Robert R. Recker^¶, Barry S. Komm, and Frederick J. Bex

From the Women's Health and Musculoskeletal Biology, Wyeth Research, Collegeville, Pennsylvania 19426, Biological Technologies, Wyeth Research, Cambridge, Massachusetts 02140, and ^¶Creighton University, Osteoporosis Research Center, Omaha, Nebraska 68131

A preliminary expression profiling analysis of osteoblasts derived from tibia explants of the high bone mass LRP5 G171V transgenic mice demonstrated increased expression of canonical Wnt pathway and Wnt/-catenin target genes compared with non-transgenic explant derived osteoblasts. Therefore, expression of Wnt/-catenin target genes were monitored after in vivo loading of the tibia of LRP5 G171V transgenic mice compared with non-transgenic mice. Loading resulted in the increased expression of Wnt pathway and Wnt/-catenin target genes including Wnt10B, SFRP1, cyclin D1, FzD2, WISP2, and connexin 43 in both genotypes; however, there was a further increased in transcriptional response with the LRP5 G171V transgenic mice. Similar increases in the expression of these genes (except cyclin D1) were observed when non-transgenic mice were pharmacologically treated with a canonical Wnt pathway activator, glycogen synthase kinase 3 inhibitor and then subjected to load. These in vivo results were further corroborated by in vitro mechanical loading experiments in which MC3T3-E1 osteoblastic cells were subjected to 3400 microstrain alone for 5 h, which increased the expression of Wnt10B, SFRP1, cyclin D1, FzD2, WISP2, and connexin 43. Furthermore, when MC3T3-E1 cells were treated with either glycogen synthase kinase 3 inhibitor or Wnt3A to activate Wnt signaling and then subjected to load, a synergistic up-regulation of these genes was observed compared with vehicle-treated cells. Collectively, the in vivo and in vitro mechanical loading results support that Wnt/-catenin signaling is a normal physiological response to load and that activation of the Wnt/-catenin pathway enhances the sensitivity of osteoblasts/osteocytes to mechanical loading.

Received for publication, March 10, 2006 , and in revised form, July 21, 2006.

^* 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.

² Both authors contributed equally to this manuscript.

³ Present address: Aventis, 1041 Rt. 202/206, N303A, Bridgewater, NJ 08807.

⁴ Present address: Dept. of Microbiology, School of Medicine, University of Washington, Seattle, WA 98195.

⁵ Present address: Amgen, Inc, 1 Amgen Center Drive, Thousand Oaks, CA 91320.

⁶ Present address: Dept. of Oral Biology, Kansas City Dental School, Kansas City, MO 64108.

¹ To whom correspondence should be addressed: Dept. Women's Health and Musculoskeletal Biology, Wyeth Research, 500 Arcola Rd., RN3247, Collegeville, PA 19426. Tel.: 484-865-2850; Fax: 484-865-9395; E-mail: robinsj{at}wyeth.com.

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