A Glanzmann's mutation in beta 3 integrin specifically impairs osteoclast function

Osteoclastic bone resorption requires cell-matrix contact, an event mediate d by the alphav beta3 integrin. The structural components of the integrin t hat mediate osteoclast function are, however, not in hand. To address this issue, we generated mice lacking the beta3 integrin gene, which have dysfun ctional 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 comple tely ineffective in restoring function to beta3(-/-) osteoclasts. To identi fy the components of the beta3 cytoplasmic domain regulating osteoclast fun ction, we generated six point mutants known, in other circumstances, to med iate 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-a ctivated signaling in the form of c-src activation. Interestingly, the doub le mutation (YF)-F-747/(YF)-F-759, which disrupts platelet function, does n ot affect the osteoclast. Thus similarities and distinctions exist in the m echanisms by which the beta3 integrin regulates platelets and osteoclasts.