Trem2 mediated Syk-dependent ROS amplification is essential for osteoclastogenesis in periodontitis microenvironment

Periodontitis is the sixth most prevalent diseases around the globe, which is closely related to many systemic diseases and affects general health. As the leading cause of tooth loss, periodontitis is characterized by irreversible alveolar bone loss and activated osteoclastogenic process, which might be closely related to the activated intracellular reactive oxygen species (ROS) in osteoclasts. Here, we demonstrated triggering receptor expressed on myeloid cells 2 (Trem2) as a key regulator of osteoclastogenesis with the regulation of intracellular ROS signals in periodontitis. In the present study, the expression of Trem2 was significantly upregulated in human alveolar bones diagnosed with chronic periodontitis, as assessed by RNA-seq. In the mice model of periodontitis, the alveolar bone resorption was impeded in the presence of the conditional knockout of Trem2 in osteoclasts. Furthermore, we identified Trem2/DAP12/Syk-dependent cascade as a vital intracellular signaling for the amplification of reactive oxygen species (ROS) signals in osteoclastogenesis, while the accumulation of soluble Aβ₄₂ oligomers (Aβo) in periodontitis microenvironment further strengthened the signals and enhanced osteoclastogenesis through direct interactions with Trem2. Collectively, Trem2 mediated ROS signal amplification cascade was crucial in the process of osteoclastogenesis in periodontitis, suggesting the potential of Trem2 as a target for the prevention and treatment of bone destruction in periodontitis.