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J. Biol. Chem., Vol. 283, Issue 9, 5866-5875, February 29, 2008

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Mechanical Stimulation of Bone in Vivo Reduces Osteocyte Expression of Sost/Sclerostin^*

Alexander G. Robling¹, Paul J. Niziolek, Lee A. Baldridge^¶, Keith W. Condon, Matthew R. Allen, Imranul Alam, Sara M. Mantila, Jelica Gluhak-Heinrich^||, Teresita M. Bellido^**, Stephen E. Harris, and Charles H. Turner

From the Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202, the Department of Biomedical Engineering; Purdue University, West Lafayette, Indiana 47907, the ^¶Department of Pathology and Laboratory Medicine; Indiana University School of Medicine, Indianapolis, Indiana 46202, the Department of Periodontics, University of Texas Health Science Center School of Dentistry, San Antonio, Texas 78229, the ^**Division of Endocrinology, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, the Department of Orthopaedic Surgery, Indiana University School of Medicine, Indianapolis, Indiana 46202, and the ^||Department of Orthodontics, University of Texas Health Science Center School of Dentistry, San Antonio, Texas 78229

Sclerostin, the protein product of the Sost gene, is a potent inhibitor of bone formation. Among bone cells, sclerostin is found nearly exclusively in the osteocytes, the cell type that historically has been implicated in sensing and initiating mechanical signaling. The recent discovery of the antagonistic effects of sclerostin on Lrp5 receptor signaling, a crucial mediator of skeletal mechanotransduction, provides a potential mechanism for the osteocytes to control mechanotransduction, by adjusting their sclerostin (Wnt inhibitory) signal output to modulate Wnt signaling in the effector cell population. We investigated the mechanoregulation of Sost and sclerostin under enhanced (ulnar loading) and reduced (hindlimb unloading) loading conditions. Sost transcripts and sclerostin protein levels were dramatically reduced by ulnar loading. Portions of the ulnar cortex receiving a greater strain stimulus were associated with a greater reduction in Sost staining intensity and sclerostin-positive osteocytes (revealed via in situ hybridization and immunohistochemistry, respectively) than were lower strain portions of the tissue. Hindlimb unloading yielded a significant increase in Sost expression in the tibia. Modulation of sclerostin levels appears to be a finely tuned mechanism by which osteocytes coordinate regional and local osteogenesis in response to increased mechanical stimulation, perhaps via releasing the local inhibition of Wnt/Lrp5 signaling.

Received for publication, June 21, 2007 , and in revised form, November 19, 2007.

^* This work was supported by National Institutes of Health Grants AR53237 (to A. G. R.), DK076007 (to T. M. B.), AR46798 (to S. E. H. and J. G.-H.), and AR046530 (to C. H. T.). 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 To whom correspondence should be addressed: Dept. of Anatomy & Cell Biology, Indiana University School of Medicine, 635 Barnhill Dr., MS 5035, Indianapolis, IN 46202. Tel.: 317-274-7489; Fax: 317-278-2040; E-mail: arobling{at}iupui.edu.