A Glanzmann's mutation in β3 integrin specifically impairs osteoclast function

Osteoclastic bone resorption requires cell-matrix contact, an event mediated by the alphav beta3 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 beta3 integrin gene, which have dysfunctional osteoclasts. Here, we show the lull rescue of beta3(-/-) osteoclast function following Expression of a full-length beta3 integrin. In contrast, truncated beta3, lacking a cytoplasmic domain (h beta3 Deltac), is completely ineffective in restoring function to beta3(-/-) osteoclasts. To identify the components of the beta3 cytoplasmic domain regulating osteoclast function, we generated six point mutants known, in other circumstances, to mediate beta integrin signaling. Of the six, only the (SP)-P-752 substitution, which also characterizes a form of the human bleeding disorder Glanzmann's thrombasthenia, fails to rescue beta3(-/-) osteoclasts or restore ligand-activated signaling in the form of c-src activation. Interestingly, the double mutation (YF)-F-747/(YF)-F-759, which disrupts platelet function, does not affect the osteoclast. Thus similarities and distinctions exist in the mechanisms by which the beta3 integrin regulates platelets and osteoclasts.