Osteocytes directly regulate osteolysis via MYD88 signaling in bacterial bone infection

Area of Science:

• Bone Biology
• Immunology
• Microbiology

Background:

• Bacterial infections can cause osteolysis, a significant bone resorption process.
• The precise role of osteocytes in bacterially-induced osteolysis is not fully understood.

Purpose of the Study:

• To investigate the direct role of osteocytes in bacterial osteolysis.
• To elucidate the signaling pathways involved in osteocyte-mediated bone resorption during infection.

Main Methods:

• Utilized mouse models with targeted genetic modifications in osteocytes (MYD88 knockout and restoration).
• Administered bacterial pathogen-associated molecular patterns (PAMPs) and Porphyromonas gingivalis (Pg) to induce osteolysis.
• Performed in vitro studies on osteocytes and osteoblasts to analyze gene expression and protein regulation.
• Assessed the efficacy of an MYD88 inhibitor in preventing bone loss.

Main Results:

• Osteocytes stimulated by PAMPs directly induce bone resorption via MYD88 signaling.
• Mice lacking osteocyte MYD88 are protected from PAMPs and Pg-induced osteolysis.
• Restoration of MYD88 in osteocytes leads to osteolysis and inflammation.
• Osteocytes up-regulate RANKL expression more than osteoblasts in response to PAMPs.
• MYD88 activation enhances CREB and STAT3 binding to Rankl enhancers and suppresses their ubiquitination.

Conclusions:

• Osteocytes are direct regulators of inflammatory osteolysis in bone infections.
• The MYD88-RANKL axis in osteocytes represents a critical pathway in bone infection.
• Targeting MYD88 and downstream RANKL regulators in osteocytes offers potential therapeutic strategies for periodontitis and osteomyelitis.