Maresin 1-LGR6 axis mitigates inflammation and posttraumatic osteoarthritis after transection of the anterior cruciate ligament in mice.

OBJECTIVE: Anterior cruciate ligament (ACL) tears frequently cause chronic inflammation and posttraumatic osteoarthritis (PTOA), with therapies failing to resolve persistent post-injury inflammation. Specialized pro-resolving mediators (SPMs), including Maresin1 (MaR1), show promise in resolving inflammation and promoting tissue repair. However, their role in PTOA remains underexplored. This study investigated inflammatory markers and MaR1 dynamics post-ACL injury, the role of the MaR1 receptor Leucine-rich Repeat-containing G protein-coupled receptor 6 (LGR6) in PTOA, and MaR1's therapeutic potential in a mouse ACL transection (ACLT) model. DESIGN: Eight-week-old C57BL6/J male mice underwent ACLT, and synovial fluid, periarticular tissue, and tibiofemoral joints were collected at various time points post-surgery for analysis. LGR6-deficient mice were utilized to investigate the role of MaR1 signaling in inflammation resolution. Additionally, the effect of intraarticular MaR1 administration on PTOA progression was assessed. RESULTS: ACLT induced joint inflammation with leukocyte infiltration and elevated pro-inflammatory cytokines. MaR1 levels peaked early post-injury and were associated with a six-fold increase in LGR6 expression. LGR6 deficiency worsened inflammation and PTOA severity with higher histological Osteoarthritis Research Society International (OARSI) scores (mean difference 5.6[95%CI: 2.5-8.6], p<0.001) and microCT OA severity scores (mean difference 4.3[95%CI: 0.7-7.9], p=0.018). Intraarticular MaR1 treatment reduced leukocyte recruitment, suppressed pro-inflammatory gene expression, and ameliorated PTOA development, improving histological OARSI scores (mean difference -3.9[95%CI: -6.9 to -1.0], p=0.012) and microCT scores (mean difference -6.7[95%CI: -10.3 to -3.0], p=0.012). CONCLUSION: This study suggests a critical role of MaR1 in resolving inflammation post-ACL injury and mitigating PTOA in mice. Targeting SPM pathways, particularly MaR1 and/or MaR1 mimetics, offers a promising strategy to prevent chronic joint inflammation and degeneration after ACL injury.