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J. Biol. Chem., Vol. 281, Issue 38, 28011-28022, September 22, 2006

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c-Src Control of Chloride Channel Support for Osteoclast HCl Transport and Bone Resorption^*

John C. Edwards, Christopher Cohen^¶, Weibing Xu^¶, and Paul H. Schlesinger^¶1

From the UNC Kidney Center and the Department of Medicine, School of Medicine, University of North Carolina, Chapel Hill, North Carolina 27599, the Department of Medicine, St. Louis University School of Medicine, St. Louis, Missouri 63104, and the ^¶Department of Physiology and Cell Biology, Washington University School of Medicine, St. Louis, Missouri 63110

Bone degradation by osteoclasts depends upon active transport of hydrogen ions to solubilize bone mineral. This transport is supported by the parallel actions of a proton ATPase and a chloride channel located in the osteoclast ruffled membrane. We have previously identified a novel chloride channel, p62, which appears to be the avian counterpart to CLIC-5b and is expressed coincident with the appearance of acid secretion as avian osteoclasts differentiate in culture. In this article, we show that suppression of CLIC-5b in differentiating avian osteoclasts results in decreased acidification by vesicles derived from these cells and decreased ability of the cells to resorb bone. Acidification is rescued by the presence of valinomycin, consistent with a selective loss of chloride channel but not proton pump activity. Osteoclast bone resorption is known to be dependent on the expression of the tyrosine kinase, c-Src. We show that CLIC-5b from osteoclasts has affinity for both Src SH2 and SH3 domains. We find that suppression of expression of Src in developing osteoclasts results in decreased vesicular acidification, which is rescued by valinomycin, consistent with the loss of chloride conductance in the proton pump-containing vesicles. Suppression of c-Src causes no change in the steady state level of CLIC-5b expression, but does result in failure of proton pump and CLIC-5b to colocalize in cultured osteoclast precursors. We conclude that suppression of c-Src interferes with osteoclast bone resorption by disrupting functional co-localization of proton pump and CLIC-5b.

Received for publication, June 19, 2006

^* This work was supported by National Institutes of Health Grant AR4653904. 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.

We dedicate this article to the memory of Christopher Cohen.

¹ To whom correspondence should be addressed. Tel.: 314-362-2223; Fax: 314-362-7463; E-mail: paul{at}cellbiology.wustl.edu.

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