CXCL9- preconditioned BMSCs attenuate rat post-traumatic osteoarthritis by modulating synovial macrophage polarization via the TLR2/TGF-β2 signaling pathway.

Abstract

Post-traumatic Osteoarthritis (PTOA) is a subtype of osteoarthritis (OA) triggered by mechanical joint injury and is characterized by pathological alterations throughout the joint, including cartilage degradation, subchondral bone remodeling, osteophyte formation, and synovitis. As a highly inflammatory subtype of OA, synovitis contributes to the progression of PTOA, with macrophages playing a pivotal role in the synovial lining. CXCL9 expression is elevated in both synovial fluid and serum of OA patients, and CXCL9 deficiency has been shown to attenuate PTOA progression in mice. However, it remains unclear whether CXCL9 can induce an immunosuppressive phenotype in bone marrow mesenchymal stem cells (BMSCs) and consequently suppress PTOA progression. This study demonstrates that ex vivo pretreatment of BMSCs with CXCL9 robustly induces an enhanced anti-inflammatory phenotype, characterized by the upregulation of key anti-inflammatory mediators. Importantly, these preconditioned BMSCs exhibit significantly enhanced capacity to polarize macrophages toward an anti-inflammatory, pro-reparative M2 phenotype in subsequent co-culture. Mechanistic investigations reveal that this enhanced effect is primarily mediated through activation of the TLR2/TGF-β2 signaling pathway within BMSCs. Finally, in a rat PTOA model, intra-articular injection of CXCL9-preconditioned BMSCs more effectively enhances M2 polarization of synovial macrophages, thereby mitigating disease progression.