Summary
We determined the role of SPM's in inflammation and analyzed their abundance in human PRP as a potential therapeutic option to treat PTOA early
Abstract
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 LGR6 in PTOA, and MaR1’s therapeutic potential in a mouse ACL transection (ACLT) model.
PRP has been postulated to be rich in SPM’s. To further take this into clinical relevance we measured SPM’s (Mar-1) in the PRP prep in patients undergoing PRP injections and identified responders versus non responders
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.
PRP from 40 patients (57.5% male; age 55.9 ± 18.0 years) was examined. The average PRP volume obtained was 7.2 ± 2.6 ml. we analyzed the PRP for responder versusu non-responder status and the amount of Mar-1 and RvD1 in order to calculate the correlations.
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 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).
IN our patient cohort the mean PRP leukocyte count was 7.6 ± 4 x 103 mm3, and mean platelet count was 8.5 ± 4.1 x 106. Mean MaR1 concentration was 667.5 ± 244.3 pg/ml (range, 349.3 to 1422.0), and mean RvD1 concentration was 139.5 ± 85.3 pg/ml (range, 41.9 to 351.2). While there was no significant correlations between SPMs levels and sex or age, correlations between MaR1 and RvD1 levels (r=0.33; p=0.04) and between MaR1 and platelet number (r=0.38; p=0.02) were found.
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. Additionally this could be easily translated into a clinical setting as PRP prearations seems to have a high abundance of Mar-1.