Osteoclastic bone resorption requires cell-matrix contact, an event mediated by the αvβ3 integrin. The structural components of the integrin that mediate osteoclast function are, however, not in hand. To address this issue, we generated mice lacking the β3 integrin gene, which have dysfunctional osteoclasts. Here, we show the full rescue of β3–/– osteoclast function following expression of a full-length β3 integrin. In contrast, truncated β3, lacking a cytoplasmic domain (hβ3Δc), is completely ineffective in restoring function to β3–/– osteoclasts. To identify the components of the β3 cytoplasmic domain regulating osteoclast function, we generated six point mutants known, in other circumstances, to mediate β integrin signaling. Of the six, only the S752P substitution, which also characterizes a form of the human bleeding disorder Glanzmann’s thrombasthenia, fails to rescue β3–/– osteoclasts or restore ligand-activated signaling in the form of c-src activation. Interestingly, the double mutation Y747F/Y759F, which disrupts platelet function, does not affect the osteoclast. Thus similarities and distinctions exist in the mechanisms by which the β3 integrin regulates platelets and osteoclasts.
Xu Feng, Deborah V. Novack, Roberta Faccio, Daniel S. Ory, Kunihiko Aya, Martin I. Boyer, Kevin P. McHugh, F. Patrick Ross, Steven L. Teitelbaum
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