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

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)
JournalJournal of Bone and Mineral Research
DOIs
StateAccepted/In press - Jan 1 2019

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src Homology Domains
Osteoclasts
Alveolar Bone Loss
Carrier Proteins
Periodontitis
Bone and Bones
Bone Resorption
Myeloid Cells
Cytokines
Macrophage Colony-Stimulating Factor
Periodontal Diseases
Syk Kinase
2-tyrosine
Osteogenesis
Protein-Tyrosine Kinases
Minerals
Ligation
Mouth
Tooth
Macrophages

Keywords

  • BONE LOSS
  • OSTEOCLASTS
  • PERIODONTITIS
  • SH3BP2
  • SYK

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Orthopedics and Sports Medicine

Cite this

Kittaka, M., Yoshimoto, T., Schlosser, C., Rottapel, R., Kajiya, M., Kurihara, H., ... Ueki, Y. (Accepted/In press). Alveolar Bone Protection by Targeting the SH3BP2-SYK Axis in Osteoclasts. Journal of Bone and Mineral Research. https://doi.org/10.1002/jbmr.3882

Alveolar Bone Protection by Targeting the SH3BP2-SYK Axis in Osteoclasts. / Kittaka, Mizuho; Yoshimoto, Tetsuya; Schlosser, Collin; Rottapel, Robert; Kajiya, Mikihito; Kurihara, Hidemi; Reichenberger, Ernst J.; Ueki, Yasuyoshi.

In: Journal of Bone and Mineral Research, 01.01.2019.

Research output: Contribution to journalArticle

Kittaka, M, Yoshimoto, T, Schlosser, C, Rottapel, R, Kajiya, M, Kurihara, H, Reichenberger, EJ & Ueki, Y 2019, 'Alveolar Bone Protection by Targeting the SH3BP2-SYK Axis in Osteoclasts', Journal of Bone and Mineral Research. https://doi.org/10.1002/jbmr.3882
Kittaka, Mizuho ; Yoshimoto, Tetsuya ; Schlosser, Collin ; Rottapel, Robert ; Kajiya, Mikihito ; Kurihara, Hidemi ; Reichenberger, Ernst J. ; Ueki, Yasuyoshi. / Alveolar Bone Protection by Targeting the SH3BP2-SYK Axis in Osteoclasts. In: Journal of Bone and Mineral Research. 2019.
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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.",
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