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Published online 22 January 2001. doi:10.1083/jcb.152.2.361
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© The Rockefeller University Press, 0021-9525/2001//361 $5.00
The Journal of Cell Biology, Volume 152, Number 2, , 2001 361-374

Original Article

Convergence of {alpha}vβ3Integrin–And Macrophage Colony Stimulating Factor–Mediated Signals on Phospholipase C{gamma} in Prefusion Osteoclasts



Ichiro Nakamuraa, Lorraine Lipferta, Gideon A. Rodana, and Le T. Duonga

a Department of Bone Biology and Osteoporosis Research, Merck Research Laboratories, West Point, Pennsylvania 19486
Department of Bone Biology and Osteoporosis Research, Merck Research Laboratories, West Point, PA 19486.(215) 652-4328(215) 652-7574

le_duong{at}merck.com

The macrophage colony stimulating factor (M-CSF) and {alpha}vβ3 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, p130Cas, paxillin, and PLC-{gamma}. However, in response to M-CSF, Src–/– pOCs spread and migrate on Vn in an {alpha}vβ3-dependent manner. Involvement of PLC-{gamma} 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 β3 integrin and PLC-{gamma} to adhesion contacts and induces stable association of β3 integrin with PLC-{gamma}, phosphatidylinositol 3-kinase, and PYK2. Moreover, direct interaction of PYK2 and PLC-{gamma} 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-{gamma} is a common downstream mediator for adhesion and growth factor signals. M-CSF–initiated signaling modulates the {alpha}vβ3 integrin-mediated cytoskeletal reorganization in prefusion osteoclasts in the absence of c-Src, possibly via PLC-{gamma}.

Key Words: {alpha}vβ3 integrins • osteoclasts • M-CSF • Src kinases • phospholipase C{gamma}

© 2001 The Rockefeller University Press

Abbreviations used in this paper: ECM, extracellular matrix; ERK, extracellular signal–regulated kinase; FAK, focal adhesion kinase; GST, glutathione S-transferase; MAP, mitogen-activated protein; M-CSF, macrophage colony stimulating factor; OCL, multinucleated osteoclast-like cell; PI 3-kinase, phosphatidylinositol 3-kinase; PL, poly-L-lysine; pOC, prefusion osteoclast-like cell; SH, src homology; TRAP, tartrate-resistant acid phosphatase; Vn, vitronectin.


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