Institute of Bone and Joint Surgery

Pre-clinical osteoarthritis (OA) models are often employed in studies investigating disease-modifying OA drugs (DMOADs). In this study, we present a comprehensive, longitudinal evaluation of OA pathogenesis including histological and biochemical analyses of articular cartilage degradation and assessment of subchondral bone sclerosis in a rat model of OA. Male Sprague-Dawley rats underwent joint destabilization surgery by anterior cruciate ligament transection and partial medial meniscectomy. The contralateral joint was evaluated as a secondary treatment, while a sham surgery was performed in independent animals (control). Further, the effects of walking on a rotating cylinder (to force mobilization of the joint) on OA pathogenesis were assessed. Destabilization-induced OA was investigated at several time points up to 20 weeks post-surgery using OARSI histopathology scores, in vivo micro-CT volumetric bone mineral density analysis and biochemical analysis of type II collagen breakdown using the CTX-II biomarker. Expression of hypertrophic chondrocyte markers was also assessed in articular cartilage. Cartilage degradation, subchondral changes, and subchondral bone loss were observed as early as 2 weeks after surgery, with considerable correlation to that seen in human OA. We found excellent correlation between histological changes and micro-CT analysis of underlying bone, which reflected properties of human OA, and identified additional molecular changes to enhance our understanding of OA pathogenesis. Interestingly, forced mobilization exercise accelerated OA progression. Minor OA activity was also observed in the contralateral joint, including proteoglycan loss. Finally, we observed increased chondrocyte hypertrophy during pathogenesis. We conclude that forced mobilization accelerates OA damage in the destabilized joint. This surgical model of OA with forced mobilization is suitable for longitudinal pre-clinical studies, and is well adapted for investigation of both early and late stages of OA. The time course of OA progression can be modulated through the use of forced mobilization.