Convergence of alpha(v)beta(3) integrin- and macrophage colony stimulatingfactor-mediated signals on phospholipase C gamma in prefusion osteoclasts

The macrophage colony stimulating factor (M-CSF) and (alpha (v)beta (3) int egrins play critical roles in osteoclast function. This study examines M-CS F- and adhesion-induced signaling in prefusion osteoclasts (pOCs) derived f rom Src-deficient and wild-type mice. Src-deficient cells attach to but do not spread on vitronectin (Vn)-coated surfaces and, contrary to wild-type c ells, their adhesion does not lead to tyrosine phosphorylation of molecules activated by adhesion, including PYK2, p130(Cas), paxillin, and PLC-gamma. However, in response to M-CSF Src(-/-) pOCs spread and migrate on Vn in an alpha (v)beta (3)-dependent manner. Involvement of PLC-gamma activation is suggested by using a PLC inhibitor, U73122, which blocks both adhesion- an d M-CSF-mediated cell spreading. Furthermore, in Src-/- pOCs M-CSF together with filamentous actin, causes recruitment of beta (3) integrin and PLC-ga mma to adhesion contacts and induces stable association of beta (3) integri n with PLC-gamma, phosphatidylinositol 3-kinase, and PYK2. Moreover, direct interaction of PYK2 and PLC-gamma can be induced by either adhesion or M-C SF suggesting that this interaction may enable the formation of integrin-as sociated complexes. Furthermore, this study suggests that in pOCs PLC-gamma is a common downstream mediator for adhesion and growth factor signals. M- CSF-initiated signaling modulates the alpha (v)beta (3) integrin-mediated c ytoskeletal reorganization in prefusion osteoclasts in the absence of c-Src , possibly via PLC-gamma.