Published 4 August 2003. doi:10.1083/jcb.200212082
© The Rockefeller University Press,
0021-9525/2003/8/499 $5.00
The Journal of Cell Biology, Volume 162, Number 3, 499-509
Dynamic changes in the osteoclast cytoskeleton in response to growth factors and cell attachment are controlled by ß3 integrin
Roberta Faccio1,3,
Deborah V. Novack1,2,
Alberta Zallone3,
F. Patrick Ross1 and
Steven L. Teitelbaum1
1 Department of Pathology, Washington University School of Medicine, St. Louis, MO 63110
2 Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110
3 Department of Human Anatomy, School of Medicine, 70124 Bari, Italy
Address correspondence to Steven L. Teitelbaum, Department of Pathology, Washington University School of Medicine, 216 South Kingshighway, St. Louis, MO 63110. Tel.: (314) 454-8463. Fax: (314) 454-5505. email: teitelbs{at}medicine.wustl.edu
The ß3 integrin cytoplasmic domain, and specifically S752, is critical for integrin localization and osteoclast (OC) function. Because growth factors such as macrophage colony–stimulating factor and hepatocyte growth factor affect integrin activation and function via inside-out signaling, a process requiring the ß integrin cytoplasmic tail, we examined the effect of these growth factors on OC precursors. To this end, we retrovirally expressed various ß3 integrins with cytoplasmic tail mutations in ß3-deficient OC precursors. We find that S752 in the ß3 cytoplasmic tail is required for growth factor–induced integrin activation, cytoskeletal reorganization, and membrane protrusion, thereby affecting OC adhesion, migration, and bone resorption. The small GTPases Rho and Rac mediate cytoskeletal reorganization, and activation of each is defective in OC precursors lacking a functional ß3 subunit. Activation of the upstream mediators c-Src and c-Cbl is also dependent on ß3. Interestingly, although the FAK-related kinase Pyk2 interacts with c-Src and c-Cbl, its activation is not disrupted in the absence of functional ß3. Instead, its activation is dependent upon intracellular calcium, and on the ß2 integrin. Thus, the ß3 cytoplasmic domain is responsible for activation of specific intracellular signals leading to cytoskeletal reorganization critical for OC function.
Key Words: osteoclast; 
vß3 integrin; M-CSF; cytoskeleton; podosome
The online version of this article includes supplemental material.
Abbreviations used in this paper: BMM, bone marrow macrophage; HGF, hepatocyte growth factor; LIBS, ligand-induced binding site; M-CSF, macrophage colony–stimulating factor; OC, osteoclast; OPN, osteopontin; VN, vitronectin.
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