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


Osteoclastic bone resorption requires cell-matrix contact, an event mediated by the alpha v beta 3 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 beta 3 integrin gene, which have dysfunctional osteoclasts. Here, we show the full rescue of beta 3(-/-) osteoclast function following expression of a full-length beta 3 integrin. In contrast, truncated beta 3, lacking a cytoplasmic domain (h beta 3c), is completely ineffective in restoring function to beta 3(-/-) osteoclasts. To identify the components of the beta 3 cytoplasmic domain regulating osteoclast function, we generated six point mutants known, in other circumstances, to mediate beta integrin signaling. Of the six, only the S(752)P substitution, which also characterizes a form of the human bleeding disorder Glanzmann's thrombasthenia, fails to rescue beta 3(-/-) osteoclasts or restore ligand-activated signaling in the form of c-src activation. Interestingly, the double mutation Y(747)F/Y(759)F, which disrupts platelet function, does not affect the osteoclast. Thus similarities and distinctions exist in the mechanisms by which the beta 3 integrin regulates platelets and osteoclasts.

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@article{Feng2001AGM, title={A Glanzmann's mutation in beta 3 integrin specifically impairs osteoclast function.}, author={X L Feng and Deborah V Novack and Roberta Faccio and Daniel S . Ory and Kunihiko Aya and Martin Boyer and Kevin P. Mchugh and Frederick P. Ross and Steven L Teitelbaum}, journal={The Journal of clinical investigation}, year={2001}, volume={107 9}, pages={1137-44} }