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J. Biol. Chem., Vol. 281, Issue 33, 23598-23605, August 18, 2006

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Expression of and Role for Ovarian Cancer G-protein-coupled Receptor 1 (OGR1) during Osteoclastogenesis^*

Meiheng Yang, Geneviève Mailhot, Mark J. Birnbaum, Carole A. MacKay, April Mason-Savas, and Paul R. Odgren¹

From the Department of Cell Biology, University of Massachusetts Medical School, Worcester, Massachusetts 01655 and Department of Biology, Merrimack College, North Andover, Massachusetts 01845

Osteoclasts differentiate from hematopoietic mononuclear precursor cells under the control of both colony stimulating factor-1 (CSF-1, or M-CSF) and receptor activator of NF-B ligand (RANKL, or TRANCE, TNFSF11) to carry out bone resorption. Using high density gene microarrays, we followed gene expression changes in long bone RNA when CSF-1 injections were used to restore osteoclast populations in the CSF-1-null toothless (csf1^tl/csf1^tl) osteopetrotic rat. We found that ovarian cancer G-protein-coupled receptor 1 (OGR1, or GPR68) was strongly up-regulated, rising >6-fold in vivo after 2 days of CSF-1 treatments. OGR1 is a dual membrane receptor for both protons (extracellular pH) and lysolipids. Strong induction of OGR1 mRNA was also observed by microarray, real-time RT-PCR, and immunoblotting when mouse bone marrow mononuclear cells and RAW 264.7 pre-osteoclast-like cells were treated with RANKL to induce osteoclast differentiation. Anti-OGR1 immunofluorescence showed intense labeling of RANKL-treated RAW cells. The time course of OGR1 mRNA expression suggests that OGR1 induction is early but not immediate, peaking 2 days after inducing osteoclast differentiation both in vivo and in vitro. Specific inhibition of OGR1 by anti-OGR1 antibody and by small inhibitory RNA inhibited RANKL-induced differentiation of both mouse bone marrow mononuclear cells and RAW cells in vitro, as evidenced by a decrease in tartrate-resistant acid phosphatase-positive osteoclasts. Taken together, these data indicate that OGR1 is expressed early during osteoclastogenesis both in vivo and in vitro and plays a role in osteoclast differentiation.

Received for publication, March 8, 2006 , and in revised form, June 6, 2006.

^* This work was supported by NIDCR, National Institutes of Health Grant DE07444 (to P. R. O.) and by core facility support provided by Diabetes Endocrinology Research Center Grant DK32520 from NIDDKD, National Institutes of Health. 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 Cell Biology, S7-242, University of Massachusetts Medical School, 55 Lake Ave. North, Worcester, MA 01655. Tel.: 508-856-8609; Fax: 508-856-1033; E-mail: paul.odgren{at}umassmed.edu.

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