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Published online March 12, 2007
doi:10.1083/jcb.200611083
The Journal of Cell Biology, Vol. 176, No. 6, 877-888
The Rockefeller University Press, 0021-9525 $30.00
© 2007 Zou et al.
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Article

 Syk, c-Src, the {alpha}vß3 integrin, and ITAM immunoreceptors, in concert, regulate osteoclastic bone resorption

Wei Zou1, Hideki Kitaura1, Jennifer Reeve1,2, Fanxin Long3, Victor L.J. Tybulewicz4, Sanford J. Shattil5, Mark H. Ginsberg5, F. Patrick Ross1, and Steven L. Teitelbaum1

1 Department of Pathology and Immunology, 2 Division of Biology and Biomedical Sciences, and 3 Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110
4 Division of Immune Cell Biology, National Institute for Medical Research, London NW7 1AA, England, UK
5 Department of Medicine, University of California, San Diego, La Jolla, CA 92093

Correspondence to Steven L. Teitelbaum: teitelbs{at}wustl.edu

In this study, we establish that the tyrosine kinase Syk is essential for osteoclast function in vitro and in vivo. Syk–/– osteoclasts fail to organize their cytoskeleton, and, as such, their bone-resorptive capacity is arrested. This defect results in increased skeletal mass in Syk–/– embryos and dampened basal and stimulated bone resorption in chimeric mice whose osteoclasts lack the kinase. The skeletal impact of Syk deficiency reflects diminished activity of the mature osteoclast and not impaired differentiation. Syk regulates bone resorption by its inclusion with the {alpha}vß3 integrin and c-Src in a signaling complex, which is generated only when {alpha}vß3 is activated. Upon integrin occupancy, c-Src phosphorylates Syk. {alpha}vß3-induced phosphorylation of Syk and the latter's capacity to associate with c-Src is mediated by the immunoreceptor tyrosine-based activation motif (ITAM) proteins Dap12 and FcR{gamma}. Thus, in conjunction with ITAM-bearing proteins, Syk, c-Src, and {alpha}vß3 represent an essential signaling complex in the bone-resorbing osteoclast, and, therefore, each is a candidate therapeutic target.

Abbreviations used in this paper: BMM, bone marrow macrophage; ITAM, immunoreceptor tyrosine-based activation motif; MCSF, macrophage colony–stimulating factor; OPG, osteoprotegrin; PTH, parathyroid hormone; RANK, receptor activator of nuclear factor {kappa}B; RANKL, RANK ligand; SFK, Src family kinase; TCL, total cell lysate; TRAP, tartrate-resistant acidic phosphatase; WT, wild type.


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