(Verbatim from the Applicant): A constant turnover of bone is required to maintain skeletal integrity. Bone turnover is accomplished with resorption by osteoclasts and synthesis by osteoblasts. When these two processes are not balanced, severe pathology commonly results, e.g. osteoporosis. Osteoclasts are large, terminally differentiated, multinucleated cells of monocytic lineage that resorb bone locally by attaching to the bone surface, acidifying the enclosed resorption space to dissolve mineral and secreting acid hydrolases into the space to digest the organic bone matrix. The molecular basis for regulating bone resorption is unknown, but important steps include the number of osteoclasts and the rate of acid secretion. Early in its resorption cycle, the osteoclast increases expression of the ruffled border proton pump. However, acid secretion by an electrogenic v-H+-ATPase is limited without a short circuit current pathway. My laboratory has identified, characterized, purified and partially cloned an outwardly rectifying chloride channel, Clor.62, that is required for the effective secretion of acid by osteoclasts. Expression of Clor.62 coincides with the ability of osteoclasts to resorb bone. Therefore, the expression and regulation of Clor.62 activity is the focus of this proposal. The oncogene src is essential to the osteoclast bone resorbing phenotype. Work in my laboratory has shown that src SH2 and SH3 domains bind Clor.62. In cultured mouse bone marrow cells, we have observed OPGL(158-315)-dependent Clor.62 expression, which is required for HCl secretion. Our hypothesis is that src and OPGL (TRANCE) are important in the late stage expression of Clor.62, which is required for HCl secretion. We propose studies to clarify the molecular basis for Clor.62 expression by osteoclasts in order to support HCl secretion in bone resorption.
| Edwards, John C; Cohen, Christopher; Xu, Weibing et al. (2006) c-Src control of chloride channel support for osteoclast HCl transport and bone resorption. J Biol Chem 281:28011-22 |
| Blair, Harry C; Borysenko, Christopher W; Villa, Anna et al. (2004) In vitro differentiation of CD14 cells from osteopetrotic subjects: contrasting phenotypes with TCIRG1, CLCN7, and attachment defects. J Bone Miner Res 19:1329-38 |
| Osman, Abdullah A; Saito, Mitsuyoshi; Makepeace, Carol et al. (2003) Wolframin expression induces novel ion channel activity in endoplasmic reticulum membranes and increases intracellular calcium. J Biol Chem 278:52755-62 |
| Blair, Harry C; Zaidi, Mone; Schlesinger, Paul H (2002) Mechanisms balancing skeletal matrix synthesis and degradation. Biochem J 364:329-41 |
