Original Article

Convergence of _vß₃ Integrin– and Macrophage Colony Stimulating Factor–mediated Signals on Phospholipase C in Prefusion Osteoclasts

Correspondence to: Le T. Duong, Department of Bone Biology and Osteoporosis Research, Merck Research Laboratories, West Point, PA 19486. Tel:(215) 652-7574 Fax:(215) 652-4328 E-mail:le_duong{at}merck.com.

The macrophage colony stimulating factor (M-CSF) and _vß₃ integrins play critical roles in osteoclast function. This study examines M-CSF– and adhesion-induced signaling in prefusion osteoclasts (pOCs) derived from 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 cells, their adhesion does not lead to tyrosine phosphorylation of molecules activated by adhesion, including PYK2, p130^Cas, paxillin, and PLC-. However, in response to M-CSF, Src^-/- pOCs spread and migrate on Vn in an _vß₃-dependent manner. Involvement of PLC- activation is suggested by using a PLC inhibitor, U73122, which blocks both adhesion- and M-CSF–mediated cell spreading. Furthermore, in Src^-/- pOCs M-CSF, together with filamentous actin, causes recruitment of ß₃ integrin and PLC- to adhesion contacts and induces stable association of ß₃ integrin with PLC-, phosphatidylinositol 3-kinase, and PYK2. Moreover, direct interaction of PYK2 and PLC- can be induced by either adhesion or M-CSF, suggesting that this interaction may enable the formation of integrin-associated complexes. Furthermore, this study suggests that in pOCs PLC- is a common downstream mediator for adhesion and growth factor signals. M-CSF–initiated signaling modulates the _vß₃ integrin-mediated cytoskeletal reorganization in prefusion osteoclasts in the absence of c-Src, possibly via PLC-.

Key Words: _vß₃ integrins, osteoclasts, M-CSF, Src kinases, phospholipase C

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