Alveolar Bone Protection by Targeting the SH3BP2-SYK Axis in Osteoclasts

Mizuho Kittaka, Tetsuya Yoshimoto, Collin Schlosser, Robert Rottapel, Mikihito Kajiya, Hidemi Kurihara, Ernst J. Reichenberger, Yasuyoshi Ueki

Research output: Contribution to journalArticle

1 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)382-395
Number of pages14
JournalJournal of Bone and Mineral Research
Volume35
Issue number2
DOIs
StatePublished - Feb 1 2020

Keywords

  • BONE LOSS
  • OSTEOCLASTS
  • PERIODONTITIS
  • SH3BP2
  • SYK

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Orthopedics and Sports Medicine

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  • Cite this

    Kittaka, M., Yoshimoto, T., Schlosser, C., Rottapel, R., Kajiya, M., Kurihara, H., Reichenberger, E. J., & Ueki, Y. (2020). Alveolar Bone Protection by Targeting the SH3BP2-SYK Axis in Osteoclasts. Journal of Bone and Mineral Research, 35(2), 382-395. https://doi.org/10.1002/jbmr.3882