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Previously, we have shown that the adaptor protein SH3-domain binding protein 2 (SH3BP2) plays a critical role in inflammatory response and osteoclastogenesis of myeloid lineage cells through spleen tyrosine kinase (SYK). In this study, we show that SH3BP2 is a novel regulator for alveolar bone resorption in periodontitis. Micro-CT analysis of SH3BP2-deficient (Sh3bp2\u2212\/\u2212) mice challenged with ligature-induced periodontitis revealed that Sh3bp2\u2212\/\u2212 mice develop decreased alveolar bone loss (male 14.9% \u00b1\u200910.2%; female 19.0% \u00b1\u20096.0%) compared with wild-type control mice (male 25.3% \u00b1\u20095.8%; female 30.8% \u00b1\u20095.8%). Lack of SH3BP2 did not change the inflammatory cytokine expression and osteoclast induction. Conditional knockout of SH3BP2 and SYK in myeloid lineage cells with LysM-Cre mice recapitulated the reduced bone loss without affecting both inflammatory cytokine expression and osteoclast induction, suggesting that the SH3BP2-SYK axis plays a key role in regulating alveolar bone loss by mechanisms that regulate the bone-resorbing function of osteoclasts rather than differentiation. Administration of a new SYK inhibitor GS-9973 before or after periodontitis induction reduced bone resorption without affecting inflammatory reaction in gingival tissues. In vitro, GS-9973 treatment of bone marrow\u2013derived M-CSF-dependent macrophages suppressed tartrate-resistant acid phosphatase (TRAP)-positive osteoclast formation with decreased mineral resorption capacity even when GS-9973 was added after RANKL stimulation. Thus, the data suggest that SH3BP2-SYK is a novel signaling axis for regulating alveolar bone loss in periodontitis and that SYK can be a potential therapeutic target to suppress alveolar bone resorption in periodontal diseases. \u00a9 2019 American Society for Bone and Mineral Research. \u00a9 2019 American Society for Bone and Mineral Research.<\/jats:p>","DOI":"10.1002\/jbmr.3882","type":"journal-article","created":{"date-parts":[[2019,10,15]],"date-time":"2019-10-15T22:00:30Z","timestamp":1571176830000},"page":"382-395","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Alveolar Bone Protection by Targeting the SH3BP2-SYK Axis in Osteoclasts"],"prefix":"10.1093","volume":"35","author":[{"given":"Mizuho","family":"Kittaka","sequence":"first","affiliation":[{"name":"Indiana Center for Musculoskeletal Health Indiana University School of Medicine Indianapolis IN USA"},{"name":"Department of Biomedical Sciences and Comprehensive Care Indiana University School of Dentistry Indianapolis IN USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tetsuya","family":"Yoshimoto","sequence":"additional","affiliation":[{"name":"Indiana Center for Musculoskeletal Health Indiana University School of Medicine Indianapolis IN USA"},{"name":"Department of Biomedical Sciences and Comprehensive Care Indiana University School of Dentistry Indianapolis IN USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Collin","family":"Schlosser","sequence":"additional","affiliation":[{"name":"Department of Orthodontics and Dentofacial Orthopedics University of Missouri-Kansas City, School of Dentistry Kansas City MO USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert","family":"Rottapel","sequence":"additional","affiliation":[{"name":"Department of Medicine, Immunology and Medical Biophysics University of Toronto Toronto Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mikihito","family":"Kajiya","sequence":"additional","affiliation":[{"name":"Department of Periodontal Medicine, Applied Life Sciences Institute of Biomedical and Health Sciences, Graduate School of Biomedical and Health Sciences, Hiroshima University Hiroshima Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hidemi","family":"Kurihara","sequence":"additional","affiliation":[{"name":"Department of Periodontal Medicine, Applied Life Sciences Institute of Biomedical and Health Sciences, Graduate School of Biomedical and Health Sciences, Hiroshima University Hiroshima Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ernst J","family":"Reichenberger","sequence":"additional","affiliation":[{"name":"Department of Reconstructive Sciences School of Dental Medicine, University of Connecticut Health Farmington CT 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