Syk, c-Src, the αvβ3 integrin, and ITAM immunoreceptors, in concert, regulate osteoclastic bone resorption

Wei Zou, Hideki Kitaura, Jennifer Reeve, Fanxin Long, Victor L.J. Tybulewicz, Sanford J. Shattil, Mark H. Ginsberg, F. Patrick Ross, Steven L. Teitelbaum

Research output: Contribution to journalArticlepeer-review

230 Citations (Scopus)


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 αvβ3 integrin and c-Src in a signaling complex, which is generated only when αvβ3 is activated. Upon integrin occupancy, c-Src phosphorylates Syk. αvβ3-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 FcRγ. Thus, in conjunction with ITAM-bearing proteins, Syk, c-Src, and αvβ3 represent an essential signaling complex in the bone-resorbing osteoclast, and, therefore, each is a candidate therapeutic target.

Original languageEnglish
Pages (from-to)877-888
Number of pages12
JournalJournal of Cell Biology
Issue number6
Publication statusPublished - 2007 Mar 12
Externally publishedYes

ASJC Scopus subject areas

  • Cell Biology


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