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Src-like adaptor protein regulates osteoclast generation and survival

Authors

  • Hyun-Ju Kim,

    Corresponding author
    1. Department of Pathology and Immunology, Washington University in St. Louis School of Medicine, St. Louis, Missouri 63110
    2. Skeletal Diseases Genome Research Center, School of Medicine, Kyungpook National University, Daegu 700-412, Korea
    • Skeletal Diseases Genome Research Center, School of Medicine, Kyungpook National University, 44-2 Samduk 2-ga, Jung-gu, Daegu 700-412, Korea.
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  • Wei Zou,

    1. Department of Pathology and Immunology, Washington University in St. Louis School of Medicine, St. Louis, Missouri 63110
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  • Yuji Ito,

    1. Department of Pathology and Immunology, Washington University in St. Louis School of Medicine, St. Louis, Missouri 63110
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  • Shin-Yoon Kim,

    1. Skeletal Diseases Genome Research Center, School of Medicine, Kyungpook National University, Daegu 700-412, Korea
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  • Jean Chappel,

    1. Department of Pathology and Immunology, Washington University in St. Louis School of Medicine, St. Louis, Missouri 63110
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  • F. Patrick Ross,

    1. Department of Pathology and Immunology, Washington University in St. Louis School of Medicine, St. Louis, Missouri 63110
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  • Steven L. Teitelbaum

    1. Department of Pathology and Immunology, Washington University in St. Louis School of Medicine, St. Louis, Missouri 63110
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Abstract

Src-like adaptor protein (SLAP) is a hematopoietic adaptor containing Src homology (SH)3 and SH2 motifs and a unique carboxy terminus. Unlike c-Src, SLAP lacks a tyrosine kinase domain. We investigated the role of SLAP in osteoclast development and resorptive function. Employing SLAP-deficient mice, we find lack of the adaptor enhances in vitro proliferation of osteoclast precursors in the form of bone marrow macrophages (BMMs), without altering their survival. Furthermore, osteoclastogenic markers appear more rapidly in SLAP−/− BMMs exposed to RANK ligand (RANKL). The accelerated proliferation of M-CSF-treated, SLAP-deficient precursors is associated with enhanced ERK activation. SLAP's role as a mediator of M-CSF signaling, in osteoclastic cells, is buttressed by complexing of the adaptor protein and c-Fms in lipid rafts. Unlike c-Src, SLAP does not impact resorptive function of mature osteoclasts but induces their early apoptosis. Thus, SLAP negatively regulates differentiation of osteoclasts and proliferation of their precursors. Conversely, SLAP decreases osteoclast death by inhibiting activation of caspase 3. These counterbalancing events yield indistinguishable bones of WT and SLAP−/− mice which contain equal numbers of osteoclasts in basal and stimulated conditions. J. Cell. Biochem. 110: 201–209, 2010. © 2010 Wiley-Liss, Inc.

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