Microbial metabolite tigloside alleviates osteoarthritis by repolarizing macrophages from M1 to M2 phenotype through...

Osteoarthritis (OA) is the most prevalent joint disease among the middle-aged and elderly individuals, primarily characterized by synovitis and cartilage damage. Although non-steroidal anti-inflammatory drugs (NSAIDs) are widely used to manage OA, they fail to fundamentally prevent or alleviate cartilage damage and can cause severe gastrointestinal or cardiovascular side effects. Therefore, developing OA drugs that address both symptoms and underlying causes is of significant importance. Our study found that tigloside (TIG), a main metabolite derived from symbiotic actinomyces, could repolarize macrophages from pro-inflammatory M1 type to anti-inflammatory M2 type, suppress the release of multiple inflammatory factors and facilitate the secretion of the anti-inflammatory cytokine IL-10, thereby creating a favorable microenvironment for chondrocyte regeneration and extracellular matrix (ECM), and alleviating pain, synovitis and OA cartilage damage. Mechanistically, TIG competes with the signaling adaptor molecule Traf1 to bind at the middle region (aa 104-414) of Trafd1, disrupting the interaction between Trafd1 and Traf1. This disruption promotes the degradation of Trafd1 and Traf1 via proteasome-ubiquitination pathway, leading to a reduction in their protein levels. Consequently, the downregulation of Trafd1 further inhibits NF-κB signaling and M1 polarization while promoting STAT6 pathway and M2 polarization, resulting in the repolarization of macrophages from M1 to M2 type and the amelioration of OA. Importantly, these findings were further validated in human macrophages derived from OA patients. In summary, this study highlights the potential of TIG as a disease-modifying drug for OA, and identifies Trafd1 as a novel therapeutic target for OA treatment.