Engagement of the osteoclast integrin α_vβ₃ by osteopontin stimulates phosphatidylinositol 3-hydroxyl kinase activity

Osteoclast adhesion via integrin α_vβ₃ to the bone matrix protein osteopontin (OPN) results in stimulation of bone resorption. We characterized an immediate signaling event that takes place upon osteoclast interaction with OPN. OPN binding to α_vβ₃ results in the rapid production of the phosphoinositides (PtdInsP), including phosphatidylinositol triphosphate (PtdIns 3,4,5P₃). Stimulation of 3,4,5-PtdInsP₃ production by OPN was produced by increased activity of PtdInsP 3-OH kinase, which was found in immunoprecipitates formed by antibodies to integrin α_vβ₃. The association of Ptdlns 3-OH kinase with integrin may have been through association with c-src. The latter was present in immunoprecipitates formed by the antibodies to integrin α_vβ₃, and src kinase was activated by OPN. These findings demonstrate a mechanism for rapid generation of cell signals upon matrix protein binding to α_vβ₃, which resembles the mechanisms used by tyrosine kinase growth factor receptors.