Bragdon, BethMekhail, Julie2024-03-062023https://hdl.handle.net/2144/48336INTRODUCTION: Anterior cruciate ligament (ACL) tears lead to joint inflammation and osteochondral degeneration culminating in posttraumatic osteoarthritis (PTOA). Inflammation resolution is actively modulated by specialized pro-resolving mediators (SPMs), fatty-acid derivatives with anti-inflammatory, analgesic, and regenerative properties. It is unknown whether SPMs play a role in PTOA. We investigated whether pro-resolving pathways are induced in a mouse model of ACL injury, focusing on maresin1 (MaR1) and resolvin D1 (RvD1), two omega-3-derived SPMs. We also investigated the sexual dimorphism in PTOA severity following ACL injury. METHODS: Eight-week-old C57BL6/J mice underwent ACLT. Joint tissues were harvested from surgical and control unoperated contralateral knee at multiple time points. Periarticular synovial tissue expression of pro-inflammatory cytokines (TNF-α, IL-1β), SPM biosynthetic enzyme (12/15Alox) and receptors (LGR6, FPR2), and synovial fluid levels of MaR1 and RvD1 were measured by qPCR and ELISA, respectively. OARSI scoring was performed by blinded observers. RESULTS: OARSI scoring and µCT scoring at 8 weeks post-injury demonstrated that ACLT induces PTOA. Thus, we assessed the acute inflammatory and pro-resolving responses to ACL injury. ACLT induced acute inflammation with increased cellular infiltrate and induction of TNF-α/IL-1β expression in the first-week post-injury. Resolvin pathways were also induced. Joint injury induced local production of synovial fluid MaR1 and RvD1, with levels peaking at 1 week after ACLT. Moreover, 12/15Alox and LGR6/FPR2 expression increase post-injury. Despite induction of SPMs, evidence of chronic inflammation persisted through week 8. µCT and histology results also showed that male mice showed more severe PTOA than female mice. CONCLUSION: Joint injury in ACLT acutely results in both inflammation and induction of the SPMs Mar1 and RvD1, as well as their biosynthetic enzymes and receptors. However, induction of these pro-resolving pathways does not completely resolve inflammation, which remains evident for months post-injury. Although the endogenous resolution response after injury is insufficient to restore tissue homeostasis and prevent damage, the existence of these pathways in the joint suggests that exogenous SPMs could be a potential intervention to reduce inflammation and damage after joint injury. Furthermore, results also suggest the presence of some protective mechanism against PTOA development in female mice in comparison to male mice.en-USAttribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/MedicineThesis/Dissertation2024-03-020009-0002-5673-7696