Osteocytes directly regulate osteolysis via MYD88 signaling in bacterial bone infection

Tetsuya Yoshimoto, Mizuho Kittaka, Andrew Anh Phuong Doan, Rina Urata, Matthew Prideaux, Roxana E. Rojas, Clifford V. Harding, W. Henry Boom, Lynda F. Bonewald, Edward M. Greenfield and Yasuyoshi Ueki ()
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Tetsuya Yoshimoto: Indiana University School of Dentistry
Mizuho Kittaka: Indiana University School of Dentistry
Andrew Anh Phuong Doan: Indiana University School of Dentistry
Rina Urata: Indiana University School of Dentistry
Matthew Prideaux: Indiana University School of Medicine
Roxana E. Rojas: Janssen Biopharma Inc
Clifford V. Harding: Case Western Reserve University & University Hospitals Cleveland Medical Center
W. Henry Boom: Case Western Reserve University & University Hospitals Cleveland Medical Center
Lynda F. Bonewald: Indiana University School of Medicine
Edward M. Greenfield: Indiana University School of Medicine
Yasuyoshi Ueki: Indiana University School of Dentistry

Nature Communications, 2022, vol. 13, issue 1, 1-19

Abstract: Abstract The 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.

Date: 2022
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DOI: 10.1038/s41467-022-34352-z

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