A Glanzmann's mutation in beta 3 integrin specifically impairs osteoclast function
Abstract
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 pla...Continue Reading
References
Isolation of monoclonal antibodies that recognize the transforming proteins of avian sarcoma viruses
Regulation of integrin affinity states through an NPXY motif in the beta subunit cytoplasmic domain.
Rescue of osteoclast function by transgenic expression of kinase-deficient Src in src-/- mutant mice
Citations
Prostate cancer specific integrin alphavbeta3 modulates bone metastatic growth and tissue remodeling
Methods Mentioned
Software Mentioned
Related Concepts
Related Feeds
Adhesion Molecules in Health and Disease
Cell adhesion molecules are a subset of cell adhesion proteins located on the cell surface involved in binding with other cells or with the extracellular matrix in the process called cell adhesion. In essence, cell adhesion molecules help cells stick to each other and to their surroundings. Cell adhesion is a crucial component in maintaining tissue structure and function. Discover the latest research on adhesion molecule and their role in health and disease here.
Blood Coagulation Signaling Pathways
Coagulation is the process by which a blood clot is formed. This process includes both the formation of a platelet plug as well as a cascade of clotting factors resulting in the formation of fibrin strands. Find the latest research on coagulation signaling pathways here.
Blood Clotting Disorders
Thrombophilia includes conditions with increased tendency for excessive blood clotting. Blood clotting occurs when the body has insufficient amounts of specialized proteins that make blood clot and stop bleeding. Here is the latest research on blood clotting disorders.