Osteocytes directly regulate osteolysis via MYD88 signaling in bacterial bone infection

dc.contributor.authorYoshimoto, Tetsuya
dc.contributor.authorKittaka, Mizuho
dc.contributor.authorDoan, Andrew Anh Phuong
dc.contributor.authorUrata, Rina
dc.contributor.authorPrideaux, Matthew
dc.contributor.authorRojas, Roxana E.
dc.contributor.authorHarding, Clifford V.
dc.contributor.authorBoom, W. Henry
dc.contributor.authorBonewald, Lynda F.
dc.contributor.authorGreenfield, Edward M.
dc.contributor.authorUeki, Yasuyoshi
dc.contributor.departmentBiomedical Sciences and Comprehensive Care, School of Dentistry
dc.date.accessioned2023-09-25T12:44:47Z
dc.date.available2023-09-25T12:44:47Z
dc.date.issued2022-11-04
dc.description.abstractThe impact of bone cell activation on bacterially-induced osteolysis remains elusive. Here, we show that matrix-embedded osteocytes stimulated with bacterial pathogen-associated molecular patterns (PAMPs) directly drive bone resorption through an MYD88-regulated signaling pathway. Mice lacking MYD88, primarily in osteocytes, protect against osteolysis caused by calvarial injections of bacterial PAMPs and resist alveolar bone resorption induced by oral Porphyromonas gingivalis (Pg) infection. In contrast, mice with targeted MYD88 restoration in osteocytes exhibit osteolysis with inflammatory cell infiltration. In vitro, bacterial PAMPs induce significantly higher expression of the cytokine RANKL in osteocytes than osteoblasts. Mechanistically, activation of the osteocyte MYD88 pathway up-regulates RANKL by increasing binding of the transcription factors CREB and STAT3 to Rankl enhancers and by suppressing K48-ubiquitination of CREB/CREB binding protein and STAT3. Systemic administration of an MYD88 inhibitor prevents jawbone loss in Pg-driven periodontitis. These findings reveal that osteocytes directly regulate inflammatory osteolysis in bone infection, suggesting that MYD88 and downstream RANKL regulators in osteocytes are therapeutic targets for osteolysis in periodontitis and osteomyelitis.
dc.eprint.versionFinal published version
dc.identifier.citationYoshimoto T, Kittaka M, Doan AAP, et al. Osteocytes directly regulate osteolysis via MYD88 signaling in bacterial bone infection. Nat Commun. 2022;13(1):6648. Published 2022 Nov 4. doi:10.1038/s41467-022-34352-z
dc.identifier.urihttps://hdl.handle.net/1805/35750
dc.language.isoen_US
dc.publisherSpringer Nature
dc.relation.isversionof10.1038/s41467-022-34352-z
dc.relation.journalNature Communications
dc.rightsAttribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.sourcePMC
dc.subjectOsteoimmunology
dc.subjectPeriodontitis
dc.subjectInfection
dc.titleOsteocytes directly regulate osteolysis via MYD88 signaling in bacterial bone infection
dc.typeArticle
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