Abstract
Preclinical 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 in a rat model of OA, including histologic and biochemical analyses of articular cartilage degradation and assessment of subchondral bone sclerosis. 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, and sham surgery was performed in a separate group of animals (controls). Furthermore, 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 after surgery using Osteoarthritis Research Society International histopathology scores, in vivo micro-computed tomography (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 histologic changes and micro-CT analysis of underlying bone, which reflected properties of human OA, and identified additional molecular changes that 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 preclinical studies, and it 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.
Highlights
D Osteoarthritis (OA) is a complex degenerative disease [1,2,3] subchondral bone of synovial joints [4,5,6,7]
Near-zero Osteoarthritis Research Society International (OARSI) scores indicated that OA activity did not occur at any point up to 20 weeks in either joint surface of NM and forced mobilization (FM) sham animals (Figure 4a,c)
Development and comprehensive characterization of pre-clinical OA models is pivotal to understanding pathology and intervention mechanisms
Summary
D Osteoarthritis (OA) is a complex degenerative disease [1,2,3] subchondral bone of synovial joints [4,5,6,7]. Before a DMOAD can reach clinical trials, it must first be successful in preclinical trials This requires animal models of OA in which specific aspects of drug efficacy in articular cartilage, subchondral bone and other affected tissues may be examined, as may potential side effects in other organs [11]. Large animals such as dogs or sheep are sometimes preferred for these purposes because they provide sufficient amounts of tissue for analysis [12]. It is advantageous to develop surgical models in rats or mice because genetic studies are possible in these animals [2931]. Specific exercise protocols [35,39] are believed to alter OA pathogenesis, longitudinal evaluation of forced mobilization (FM) has never been investigated
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