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

  • J Bone Miner Res. 2020 Feb;35(2):382-395. doi: 10.1002/jbmr.3882.
Mizuho Kittaka  1  2 ,  Tetsuya Yoshimoto  1  2 ,  Collin Schlosser  3 ,  Robert Rottapel  4 ,  Mikihito Kajiya  5 ,  Hidemi Kurihara  5 ,  Ernst J Reichenberger  6 ,  Yasuyoshi Ueki  1  2
Affiliations
  • 1. Department of Biomedical Sciences and Comprehensive Care, Indiana University School of Dentistry, Indianapolis, IN, USA.
  • 2. Indiana Center for Musculoskeletal Health, Indiana University School of Medicine, Indianapolis, IN, USA.
  • 3. Department of Orthodontics and Dentofacial Orthopedics, University of Missouri-Kansas City, School of Dentistry, Kansas City, MO, USA.
  • 4. Department of Medicine, Immunology and Medical Biophysics, University of Toronto, Toronto, Canada.
  • 5. Department of Periodontal Medicine, Applied Life Sciences, Institute of Biomedical and Health Sciences, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
  • 6. Department of Reconstructive Sciences, School of Dental Medicine, University of Connecticut Health, Farmington, CT, USA.
PMID: 31613396 DOI: 10.1002/jbmr.3882
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. © 2019 American Society for Bone and Mineral Research. © 2019 American Society for Bone and Mineral Research.

Keywords
BONE LOSS; OSTEOCLASTS; PERIODONTITIS; SH3BP2; SYK.
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