Osteomyelitis and periodontitis are bacterial diseases that impact the skeleton, leading to severe inflammatory osteolysis. While osteocytes are known to produce a wide range of inflammatory mediators in response to microbial pathogens and are the primary source of RANKL responsible for osteoclastogenesis, it remains unclear if osteocytes can function as inflammatory cells in conditions such as osteomyelitis and periodontitis. Additionally, the molecular mechanisms osteocytes utilize are not well understood. As osteocytes express toll-like receptor 2 (TLR2) and its signal transducer MYD88, we created Dmp1-Cre;Myd88lsl/lsl(loxP-stop-loxP) mice, in which MYD88 function is restored predominantly in osteocytes. Injection of a TLR1/2 agonist Pam3CSK4 onto calvaria or induction of periodontitis by oral infection with P.gingivalis(Pg), one of the most common human bacteria causing periodontitis responsible for alveolar bone loss in a TLR2-dependent manner, resulted in significant osteolysis comparable to Myd88+/+ mice. In both models, Dmp1-Cre;Myd88lsl/lsl mice exhibited increased Rankl expression and osteoclast induction in bone tissues. H&E staining showed considerable infiltration of inflammatory cells on the calvaria of Pam3CSK4-injected Dmp1-Cre;Myd88lsl/lsl mice. Expression levels of inflammatory cytokines, such as Tnf and Il1b, were increased in skin lesions overlying the calvaria of Pam3CSK4-injected Dmp1-Cre;Myd88lsl/lsl mice and in gingival tissues of Pg-infected Dmp1-Cre;Myd88lsl/lsl mice compared to Myd88lsl/lsl mice treated with Pam3CSK4 or Pg. Immunohistochemical staining and qPCR analysis of skin lesions revealed that calvarial lesions of Pam3-injected Dmp1-Cre;Myd88lsl/lsl mice contain large numbers of cells positive for F4/80 or Ly6G, a marker for macrophages and neutrophils, respectively. Inflamed osteocytes increased chemotaxis of neutrophils and macrophages in response to Pam3CSK4. Collectively, these results suggest that inflamed osteocytes directly contribute to inflammatory osteolysis through MYD88 signaling in bacterial bone infection. The osteocyte MYD88 pathway and osteocyte-derived inflammatory factors that regulate immune cell activation may be potential therapeutic targets for osteolysis caused by bacterial infection, as seen in osteomyelitis and periodontitis.