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J. Biol. Chem., Vol. 282, Issue 28, 20715-20727, July 13, 2007

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Wnt/-Catenin Signaling Is a Component of Osteoblastic Bone Cell Early Responses to Load-bearing and Requires Estrogen Receptor ^*

From the Department of Veterinary Basic Sciences, The Royal Veterinary College, London NW1 0TU, United Kingdom

The Wnt/-catenin pathway has been implicated in bone cell response to their mechanical environment. This response is the origin of the mechanism by which bone cells adjust bone architecture to maintain bone strength. Osteoporosis is the most widespread failure of this mechanism. The degree of osteoporotic bone loss in men and women is related to bio-available estrogen. Here we report that in osteoblastic ROS 17/2.8 cells and primary osteoblast cultures, a single short period of dynamic mechanical strain, as well as the glycogen synthase kinase-3 (GSK-3) inhibitor LiCl, increased nuclear accumulation of activated -catenin and stimulated TCF/LEF reporter activity. This effect was blocked by the estrogen receptor (ER) modulators ICI 182,780 and tamoxifen and was absent in primary osteoblast cultures from mice lacking ER. Microarray expression data for 25,000 genes from total RNA extracted from tibiae of wild-type mice within 24 h of being loaded in vivo showed differential gene regulation between loaded and contralateral non-loaded bones of 10 genes established to be involved in the Wnt pathway. Only 2 genes were involved in loaded tibiae from mice lacking ER (ER^-/-). Together these data suggest that Wnt/-catenin signaling contributes to bone cell early responses to mechanical strain and that its effectiveness requires ER. Reduced effectiveness of bone cell responses to bone loading, associated with estrogen-related decline in ER, may contribute to the failure to maintain structurally appropriate bone mass in osteoporosis in both men and women.

Received for publication, April 17, 2007 , and in revised form, May 8, 2007.

^* This work was supported by The Wellcome Trust. 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.

¹ A BBSRC research student.

² To whom correspondence should be addressed: Dept. of Veterinary Basic Sciences, The Royal Veterinary College, Royal College St., London, NW1 0TU, UK. Tel.: 44-207-468-5000; Fax: 44-207-468-5304; E-mail: llanyon{at}rvc.ac.uk.

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