Browsing by Author "Schlosser, Collin"

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    Alveolar bone protection by targeting the SH3BP2-SYK axis in osteoclasts
    (Wiley, 2020-02) Kittaka, Mizuho; Yoshimoto, Tetsuya; Schlosser, Collin; Rottapel, Robert; Kajiya, Mikihito; Kurihara, Hidemi; Reichenberger, Ernst J.; Ueki, Yasuyoshi; Biomedical Sciences and Comprehensive Care, School of Dentistry
    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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    Microbe-Dependent Exacerbated Alveolar Bone Destruction in Heterozygous Cherubism Mice
    (American Society for Bone and Mineral Research, 2020-02-24) Kittaka, Mizuho; Yoshimoto, Tetsuya; Schlosser, Collin; Kajiya, Mikihito; Kurihara, Hidemi; Reichenberger, Ernst J.; Ueki, Yasuyoshi; Biomedical Sciences and Comprehensive Care, School of Dentistry
    Cherubism (OMIM#118400) is a craniofacial disorder characterized by destructive jaw expansion. Gain‐of‐function mutations in SH3‐domain binding protein 2 (SH3BP2) are responsible for this rare disorder. We have previously shown that homozygous knock‐in (KI) mice (Sh3bp2 KI/KI) recapitulate human cherubism by developing inflammatory lesions in the jaw. However, it remains unknown why heterozygous KI mice (Sh3bp2 KI/+) do not recapitulate the excessive jawbone destruction in human cherubism, even though all mutations are heterozygous in humans. We hypothesized that Sh3bp2 KI/+ mice need to be challenged for developing exacerbated jawbone destruction and that bacterial stimulation in the oral cavity may be involved in the mechanism. In this study, we applied a ligature‐induced periodontitis model to Sh3bp2 KI/+ mice to induce inflammatory alveolar bone destruction. Ligature placement induced alveolar bone resorption with gingival inflammation. Quantification of alveolar bone volume revealed that Sh3bp2 KI/+ mice developed more severe bone loss (male: 43.0% ± 10.6%, female: 42.6% ± 10.4%) compared with Sh3bp2 +/+ mice (male: 25.8% ± 4.0%, female: 30.9% ± 6.5%). Measurement of bone loss by the cement‐enamel junction–alveolar bone crest distance showed no difference between Sh3bp2 KI/+ and Sh3bp2 +/+ mice. The number of osteoclasts on the alveolar bone surface was higher in male Sh3bp2 KI/+ mice, but not in females, compared with Sh3bp2 +/+ mice. In contrast, inflammatory cytokine levels in gingiva were comparable between Sh3bp2 KI/+ and Sh3bp2 +/+ mice with ligatures. Genetic deletion of the spleen tyrosine kinase in myeloid cells and antibiotic treatment suppressed alveolar bone loss in Sh3bp2 KI/+ mice, suggesting that increased osteoclast differentiation and function mediated by SYK and accumulation of oral bacteria are responsible for the increased alveolar bone loss in Sh3bp2 KI/+ mice with ligature‐induced periodontitis. High amounts of oral bacterial load caused by insufficient oral hygiene could be a trigger for the initiation of jawbone destruction in human cherubism.