Microbe-Dependent Exacerbated Alveolar Bone Destruction in Heterozygous Cherubism Mice

dc.contributor.authorKittaka, Mizuho
dc.contributor.authorYoshimoto, Tetsuya
dc.contributor.authorSchlosser, Collin
dc.contributor.authorKajiya, Mikihito
dc.contributor.authorKurihara, Hidemi
dc.contributor.authorReichenberger, Ernst J.
dc.contributor.authorUeki, Yasuyoshi
dc.contributor.departmentBiomedical Sciences and Comprehensive Care, School of Dentistryen_US
dc.date.accessioned2020-10-08T16:39:53Z
dc.date.available2020-10-08T16:39:53Z
dc.date.issued2020-02-24
dc.description.abstractCherubism (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.en_US
dc.identifier.citationKittaka, M., Yoshimoto, T., Schlosser, C., Kajiya, M., Kurihara, H., Reichenberger, E. J., & Ueki, Y. (2020). Microbe-Dependent Exacerbated Alveolar Bone Destruction in Heterozygous Cherubism Mice. JBMR Plus, 4(6), e10352. https://doi.org/10.1002/jbm4.10352en_US
dc.identifier.issn2473-4039en_US
dc.identifier.urihttps://hdl.handle.net/1805/24015
dc.language.isoen_USen_US
dc.publisherAmerican Society for Bone and Mineral Researchen_US
dc.relation.isversionof10.1002/jbm4.10352en_US
dc.relation.journalJBMR Plusen_US
dc.rightsAttribution 4.0 International*
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/*
dc.sourcePMCen_US
dc.subjectCHERUBISMen_US
dc.subjectORAL MICROBESen_US
dc.subjectOSTEOCLASTSen_US
dc.subjectPERIODONTITISen_US
dc.subjectSH3BP2en_US
dc.titleMicrobe-Dependent Exacerbated Alveolar Bone Destruction in Heterozygous Cherubism Miceen_US
dc.typeArticleen_US
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