Synovial Fluid‐derived Micrococcus Luteus G18 Exacerbates Osteoarthritis Progression by Promoting Chondrocyte Degradation via TLR2/JNK/AP‐1 Signaling Pathway

Traditionally considered sterile, the articular cavity is now recognized to harbor microbial communities influencing osteoarthritis (OA). Integrating 16S rRNA sequencing and culturomics, Micrococcus luteus is enriched in advanced OA. Notably, M. luteus G18 exacerbates cartilage degeneration via TLR2/JNK/AP‐1‐mediated ECM disruption, revealing intra‐articular microbiota as previously unrecognized pivotal contributors to OA pathogenesis with promising diagnostic and therapeutic potential. Abstract Traditionally considered a sterile environment, the articular cavity has this perception overturned with advances in multi‐omics technologies—microbial communities are increasingly identified in once‐thought sterile tissues, making the articular cavity a potential microbial niche. However, the presence and role of intra‐articular microbes in osteoarthritis (OA) remain rarely studied. Synovial fluid microbiomes of OA patients at different stages are analyzed via 16S rRNA high‐throughput sequencing, and the results show that microbial diversity is positively correlated with OA progression, with the microbiomes dominated by Proteobacteria, Firmicutes, and Actinobacteria. Culturing yields 145 strains, with Micrococcus luteus (M. luteus) significantly enriched in advanced OA. In OA rats, intra‐articular transplantation of synovial microbes or M. luteus G18 exacerbates cartilage damage. Mechanistically, M. luteus G18 activates the TLR2/JNK/AP‐1 pathway via surface peptidoglycan, disrupting chondrocyte homeostasis to inhibit extracellular matrix (ECM) synthesis and promote degradation. These findings not only provide the first comprehensive evidence of the joint cavity microbiota but also unveil M. luteus G18 as a microbial driver of OA progression. This study reshapes the understanding of OA pathogenesis and opens new avenues for microbial‐based diagnostics and therapeutics—pointing toward a previously overlooked dimension of joint biology that deserves further exploration. Traditionally considered sterile, the articular cavity is now recognized to harbor microbial communities influencing osteoarthritis (OA). Integrating 16S rRNA sequencing and culturomics, Micrococcus luteus is enriched in advanced OA. Notably, M. luteus G18 exacerbates cartilage degeneration via TLR2/JNK/AP-1-mediated ECM disruption, revealing intra-articular microbiota as previously unrecognized pivotal contributors to OA pathogenesis with promising diagnostic and therapeutic potential. Abstract Traditionally considered a sterile environment, the articular cavity has this perception overturned with advances in multi-omics technologies—microbial communities are increasingly identified in once-thought sterile tissues, making the articular cavity a potential microbial niche. However, the presence and role of intra-articular microbes in osteoarthritis (OA) remain rarely studied. Synovial fluid microbiomes of OA patients at different stages are analyzed via 16S rRNA high-throughput sequencing, and the results show that microbial diversity is positively correlated with OA progression, with the microbiomes dominated by Proteobacteria, Firmicutes, and Actinobacteria. Culturing yields 145 strains, with Micrococcus luteus (M. luteus) significantly enriched in advanced OA. In OA rats, intra-articular transplantation of synovial microbes or M. luteus G18 exacerbates cartilage damage. Mechanistically, M. luteus G18 activates the TLR2/JNK/AP-1 pathway via surface peptidoglycan, disrupting chondrocyte homeostasis to inhibit extracellular matrix (ECM) synthesis and promote degradation. These findings not only provide the first comprehensive evidence of the joint cavity microbiota but also unveil M. luteus G18 as a microbial driver of OA progression. This study reshapes the understanding of OA pathogenesis and opens new avenues for microbial-based diagnostics and therapeutics—pointing toward a previously overlooked dimension of joint biology that deserves further exploration. Advanced Science, EarlyView.