2. Academic Validation
  3. Osteocytes directly regulate osteolysis via MYD88 signaling in bacterial bone infection

Osteocytes directly regulate osteolysis via MYD88 signaling in bacterial bone infection

  • Nat Commun. 2022 Nov 4;13(1):6648. doi: 10.1038/s41467-022-34352-z.
Tetsuya Yoshimoto 1 2,  Mizuho Kittaka 1 2,  Andrew Anh Phuong Doan 1 2,  Rina Urata 1 2,  Matthew Prideaux 2 3,  Roxana E Rojas 4,  Clifford V Harding 5,  W Henry Boom 5 6 7,  Lynda F Bonewald 2 3,  Edward M Greenfield 2 3 8,  Yasuyoshi Ueki 9 10
Affiliations

Affiliations

  • 1 Department of Biomedical Sciences and Comprehensive Care, Indiana University School of Dentistry, Indianapolis, IN, 46202-5126, USA.
  • 2 Indiana Center for Musculoskeletal Health, Indiana University School of Medicine, Indianapolis, IN, 46202-5126, USA.
  • 3 Department of Anatomy, Cell Biology, and Physiology, Indiana University School of Medicine, Indianapolis, IN, 46202-5126, USA.
  • 4 Janssen Biopharma Inc, Brisbane, CA, 94005-1809, USA.
  • 5 Department of Pathology, Case Western Reserve University & University Hospitals Cleveland Medical Center, Cleveland, OH, 44106-4960, USA.
  • 6 Department of Medicine, Case Western Reserve University & University Hospitals Cleveland Medical Center, Cleveland, OH, 44106-4960, USA.
  • 7 Department of Molecular Biology and Microbiology, Case Western Reserve University & University Hospitals Cleveland Medical Center, Cleveland, OH, 44106-4960, USA.
  • 8 Department of Orthopaedic Surgery, Indiana University School of Medicine, Indianapolis, IN, 46202-5126, USA.
  • 9 Department of Biomedical Sciences and Comprehensive Care, Indiana University School of Dentistry, Indianapolis, IN, 46202-5126, USA. uekiy@iu.edu.
  • 10 Indiana Center for Musculoskeletal Health, Indiana University School of Medicine, Indianapolis, IN, 46202-5126, USA. uekiy@iu.edu.
PMID: 36333322 DOI: 10.1038/s41467-022-34352-z
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.

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