Background/Purpose: Animal models of osteoarthritis(OA) are used extensively in research of its pathogenesis and in search of disease modifying anti-OA drugs. However, whether current animal models of OA properly represent human OA is a critical question. In devising an animal model which can be extrapolated into human disease, 2 factors, obesity and bipedal walking inherent in human locomotion have been under-reporesented. In this study, we sought to investigate the influence of obligatory bipedal walking on OA development in C57BL6 mice.  In addition, by inducing obesity, we observed whether excess body weight acts synergistically with bipedal walking in the development of OA.

Methods: Seventy-two 31 week-old C57BL6 mice were divided into 2 groups and one group was fed with 30% fat diet and another group with control diet for 2 months. After induction of obesity, mice from each group were again divided into 2 groups and obligatory bipedal exercise was induced with specially designed treadmill for 1-4 hours daily in each group, resulting in 4 experimental groups of mice (control, control bipedal, obese, obese bipedal). After 8,10 and 12 weeks of bipedal walking, animals were sacrificed. Knee joints were obtained and graded microscopically according to scoring system recommended by OARSI histopathology initiative and modified Mankin score. Serum levels of cartilage oligomeric matrix protein(COMP) and type II collagen degradation product were measured with ELISA. Pain behavior was assessed with von Frey fiber test and regularity index measured by catwalk test.

Results: High fat diet for 2 months induced significant weight gain in C57BL6 mice without signs of physical illness. Typical findings of human OA cartilage, including surface fibrillation, proteoglycan matrix depletion and chondrocyte loss began to appear after 8 weeks of exercise in bipedal groups and progressed as the duration of exercise increased. At 12 weeks, vertical erosion to calficifed cartilage typical of mouse OA was observed in none of control and obese groups, and in 66.6 and 100% of control bipedal and obese bipedal groups.  OA grading was significantly higher in bipedal groups compared to obese and control groups, and significantly higher in obese bipedal group compared to control bipedal group. OA change in bipedal groups was accompanied by synovitis and subchondroal bone thickening while osteophyte formation was not significantly increased. OA grading was not significantly different between obese and control group.  Serum levels of COMP were significantly increased in bipedal groups compared to control or obese group at 8 and 10 weeks of exercise. Threshold for von Frey fiber test decreased significantly in bipedal groups compared to control group while it significantly increased in obese group.  Abnormal gait pattern measured by regularity index in catwalk test tended to increase in obese bipedal group compared to other groups.  

Conclusion: By induction of obesity and bipedal exercise, natural OA mimicking human OA was induced in C57BL7 mouse. The regulation of relevant signaling mechanism during progression of OA in this model would contribute to the understanding of pathogenetic mechanism of human OA and efficient evaluation of novel therapeutic agents.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/development-of-a-mouse-model-of-natural-osteoarthritis-of-knee-by-induction-of-obesity-and-bipedal-walking/