Structural osteoarthritis pathogenesis correlates with distinct pain and dysfunction profiles after ACL injury in rats

Post-traumatic osteoarthritis (PTOA) frequently arises following knee injury, such as anterior cruciate ligament (ACL) rupture. Small animal models are critical for studying PTOA pathology and translating therapeutic interventions. Here our objective was to identify key structural PTOA pathologies and evaluate their associations with aberrant pain and function after a clinically relevant ACL injury in a small animal model. This work leveraged a suite of quantitative cartilage and bone analysis techniques using high-resolution contrast-enhanced microcomputed tomography to investigate the associations between pain-related behaviors and structural osteoarthritis pathogenesis throughout the knee joint in rats. We hypothesized that ACL rupture would increase pain sensitization and limb dysfunction and that this would correlate with the development of clinically relevant osteophytes and cartilage lesions at moderate (4 weeks) and severe disease stages (8 weeks). We showed that ACL rupture induced hyperalgesia and prolonged hindlimb weight-bearing dysfunction; these pain-related behaviors were strongly correlated with changes in the tibiofemoral subchondral bone plate, but not with osteophyte formation. Moreover, we show that patella bone pathology correlates strongly with pain sensitivity and limb function. Joint degeneration initially manifested in the posterior aspect of the medial tibiofemoral compartments, as indicated by full-thickness femoral cartilage lesions and tibial osteophytes at 4 weeks and corresponding tibial cartilage hypertrophy and subchondral sclerosis by 8 weeks. The established outcome parameters and association of structural pathogenesis with pain and dysfunction provide a foundation for studying fundamental PTOA disease etiology and testing therapeutic efficacy in a rodent preclinical model.