THE IMPACT OF JOINT INJURY Understanding the Role of Injury Mechanism in the Structural and Symptomatic Progression of Osteoarthritis Using Mouse Models of Knee Injury

Abstract

Post-traumatic osteoarthritis (PTOA) accounts for approximately 12% of all lower limb OA. Compared to other OA-phenotypes PTOA has the advantage of a known initiating event/time, enabling early identification of at-risk patients. However, with only ~50% of those with apparently similar joint injuries progressing to PTOA, one of the challenges in the field is defining the factors which separate progressors from non-progressors. Do these factors involve tissue-specific injury; biomechanical instability; or the impact trauma at the time of injury? The aims of this thesis were to investigate the role of injury mechanism on the progression of PTOA through the assessment of structural, symptomatic and biomechanical changes in three mouse models of knee injury: (1) surgical ACL transection (ACLT: joint instability, no impact trauma), (2) mechanical ACL rupture (ACLR: joint instability plus a single impact trauma) and (3) sub-critical knee injury (no joint instability, single impact trauma). The two mouse models of ACL injury (ACLT, ACLR) replicated variable PTOA risk seen in patients. Similar to ACL injured patients, joint instability and symptoms (pain/sensitization) were not related to tissue-specific pathologies or structural PTOA progression. Specific tissue pathologies and their associations were identified in the more progressive ACLR model, aligning with OA-cartilage risk factors in patients: synovial inflammation, subchondral bone remodelling, and meniscal pathology. The interaction of OA pathology both within and between knee compartments was found to be dependent on injury mechanism, but not instability or pain. The role and consequences of loading history in joint degeneration was explored in the sub-critical joint injury model. While a single loading event did not induce PTOA, it resulted in focal osteochondral lesions, reduced ACL strength, and altered joint sensitisation. The results of this thesis highlight the importance of joint injury mechanism on PTOA risk, defining key injury- and compartment-specific joint tissue pathology associations, and identifying sub-critical injuries as risk factors for both critical injury and subsequent PTOA.