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SLP-76 Couples Syk to the Osteoclast Cytoskeleton¹

Jennifer L. Reeve^*,, Wei Zou^*, Yuli Liu^*, Jonathan S. Maltzman, F. Patrick Ross^* and Steven L. Teitelbaum^2,*

*Department of Pathology and Immunology and Division of Biology and Biomedical Science, Washington University School of Medicine, St. Louis, MO 63110; and Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104

The capacity of the osteoclast (OC) to resorb bone is dictated by cytoskeletal organization, which in turn emanates from signals derived from the _vβ₃ integrin and c-Fms. Syk is key to these signals and, in other cells, this tyrosine kinase exerts its effects via intermediaries including the SLP adaptors, SLP-76 and BLNK (B cell linker). Thus, we asked whether these two SLP proteins regulate OC function. We find BLNK-deficient OCs are normal, whereas cytoskeletal organization of those lacking SLP-76 is delayed, thus modestly reducing bone resorption in vitro. Cytoskeletal organization and bone resorption are more profoundly arrested in cultured OCs deficient in BLNK and SLP-76 double knockout (DKO) phenotypes. In contrast, stimulated bone resorption in vivo is inhibited 40% in either SLP-76^–/– or DKO mice. This observation, taken with the fact that DKO OCs are rescued by retroviral transduction of only SLP-76, indicates that SLP-76 is the dominant SLP family member in the resorptive process. We also find SLP-76 is phosphorylated in a Syk-dependent manner. Furthermore, in the absence of the adaptor protein, integrin-mediated phosphorylation of Vav3, the OC cytoskeleton-organizing guanine nucleotide exchange factor, is abrogated. In keeping with a central role of SLP-76/Vav3 association in osteoclastic resorption, retroviral transduction of SLP-76, in which the Vav binding site is disrupted (3YF), fails to normalize the cytoskeleton of DKO OCs and the resorptive capacity of the cells. Finally, c-Fms-activated Syk also exerts its OC cytoskeleton-organizing effect in a SLP-76/Vav3-dependent manner.

² Address correspondence and reprint requests to Dr. Steven L. Teitelbaum, Department of Pathology and Immunology, Washington University School of Medicine, Campus Box 8118, 660 South Euclid Avenue, St. Louis, MO 63110. E-mail address: teitelbs{at}wustl.edu

¹ This work was supported by Grant 8590 from the Shriners' Hospitals for Children (to S.L.T.) and Grants AR032788 and AR046523 (to S.L.T.), Grant AR046852 (to F.P.R.), and Grant 1 F30 AG302802 (to J.L.R.) from the National Institutes of Health. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health.