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J. Biol. Chem., Vol. 281, Issue 3, 1412-1418, January 20, 2006

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Mechanical Inhibition of RANKL Expression Is Regulated by H-Ras-GTPase^*

Janet Rubin1, Tamara C. Murphy, Jill Rahnert, Hannah Song, Mark S. Nanes, Edward M. Greenfield¶, Hanjoong Jo, and Xian Fan

From the Department of Medicine, Emory University School of Medicine and Veterans Affairs Medical Center, Atlanta, Georgia 30033, the ^¶Department of Orthopaedics, Case Western Reserve University, Cleveland, Ohio 44106, and the Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, Georgia 30322

Mechanical input is known to regulate bone remodeling, yet the molecular events involved in mechanical signal transduction are poorly understood. We here investigate proximal events leading to the ERK1/2 activation that is required for mechanical repression of RANKL (receptor activator of NF-B ligand) expression, the factor that controls local recruitment of osteoclasts. Using primary murine bone stromal cells we show that dynamic mechanical strain via substrate deformation activates Ras-GTPase, in particular the H-Ras isoform. Pharmacological inhibition of H-Ras function prevents strain activation of H-Ras as well as the downstream mechanical repression of RANKL. Furthermore, small interfering RNA silencing of H-Ras, but not K-Ras, abrogates mechanical strain repression of RANKL. H-Ras-specific inhibition of mechanorepression of RANKL was also demonstrated in a murine pre-osteoblast cell line (CIMC-4). The requirement of cholesterol for H-Ras activation was probed; cholesterol depletion of rafts using methyl-cyclodextrin prevented mechanical H-Ras activation. That the mechanical repression of RANKL requires activation of H-Ras, a specific isoform of Ras-GTP that is known to reside in the lipid raft microdomain, suggests that spatial arrangements are critical for generation of specific downstream events in response to mechanical signals. By partitioning signals this way, cells may be able to generate different downstream responses through seemingly similar signaling cascades.

Received for publication, August 5, 2005 , and in revised form, November 22, 2005.

^* This work was supported by National Institutes of Health Grant AR 042360 and a Veterans Affairs Merit Review. 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: VAMC-151, 1670 Clairmont Rd., Decatur, GA 30033. Tel.: 404-321-6111 (ext. 2080); E-mail: janet.rubin{at}emory.edu.

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