Alveolar bone protection by targeting the SH3BP2-SYK axis in osteoclasts
dc.contributor.author | Kittaka, Mizuho | |
dc.contributor.author | Yoshimoto, Tetsuya | |
dc.contributor.author | Schlosser, Collin | |
dc.contributor.author | Rottapel, Robert | |
dc.contributor.author | Kajiya, Mikihito | |
dc.contributor.author | Kurihara, Hidemi | |
dc.contributor.author | Reichenberger, Ernst J. | |
dc.contributor.author | Ueki, Yasuyoshi | |
dc.contributor.department | Biomedical Sciences and Comprehensive Care, School of Dentistry | en_US |
dc.date.accessioned | 2022-05-19T18:25:41Z | |
dc.date.available | 2022-05-19T18:25:41Z | |
dc.date.issued | 2020-02 | |
dc.description.abstract | Periodontitis is a bacterially induced chronic inflammatory condition of the oral cavity where tooth-supporting tissues including alveolar bone are destructed. 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 -/- ) mice challenged with ligature-induced periodontitis revealed that Sh3bp2 -/- mice develop decreased alveolar bone loss (male 14.9% ± 10.2%; female 19.0% ± 6.0%) compared with wild-type control mice (male 25.3% ± 5.8%; female 30.8% ± 5.8%). 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-derived 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. | en_US |
dc.eprint.version | Author's manuscript | en_US |
dc.identifier.citation | Kittaka M, Yoshimoto T, Schlosser C, et al. Alveolar Bone Protection by Targeting the SH3BP2-SYK Axis in Osteoclasts. J Bone Miner Res. 2020;35(2):382-395. doi:10.1002/jbmr.3882 | en_US |
dc.identifier.uri | https://hdl.handle.net/1805/29089 | |
dc.language.iso | en_US | en_US |
dc.publisher | Wiley | en_US |
dc.relation.isversionof | 10.1002/jbmr.3882 | en_US |
dc.relation.journal | Journal of Bone and Mineral Research | en_US |
dc.rights | Publisher Policy | en_US |
dc.source | PMC | en_US |
dc.subject | Periodontitis | en_US |
dc.subject | Bone loss | en_US |
dc.subject | Osteoclasts | en_US |
dc.title | Alveolar bone protection by targeting the SH3BP2-SYK axis in osteoclasts | en_US |
dc.type | Article | en_US |