Development of a mouse model of osteoarthritis of knee by induction of obesity and bipedal walking = 비만 유도 및 사람의 두발 보행에 근거한 쥐의 슬관절 골관절염 모델 개발

다국어 초록 (Multilingual Abstract)

Background/purpose: Animal models of osteoarthritis (OA) are used extensively in research of its pathogenesis and in search of potential 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- represented. In this study, we sought to investigate the influence of obligatory bipedal walking on OA development in C57BL/6 mice. In addition, by inducing obesity with high fat diet, we observed whether excess body weight acts synergistically with bipedal walking in the development of OA.
Method: Seventy two 24 week-old C57BL/6 mice were divided into 2 groups and one group was fed with 60% 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, 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 and taken the micro-computed tomography (CT). Pain behavior was observed with von Frey fiber test
Results: High fat diet for 2 months induced significant weight gain in C57BL/6 mouse without any obvious 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 calcified cartilage typical of mouse OA was only observed in bipedal animals. Cartilage grading was significantly higher in bipedal groups compared to control groups, and significantly higher in obese bipedal group compared to control bipedal group. Threshold for von Frey fiber test decreased significantly in bipedal groups compared to control group while it significantly increased in obese group.
Conclusion: By induction of obesity and bipedal exercise, natural OA mimicking human OA was induced in C57BL/6 mouse. The regulation of relevant molecular markers and 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.

목차 (Table of Contents)

• Ⅰ.서론 1
• Ⅱ.연구 대상 및 방법 4
• 1. 실험동물 4
• 2. 조직학적 분석 7
• 3. micro CT 8
• 4.mechanical allodynia 9
• 5. 통계방법 10
• Ⅲ. 연구 결과 11
• 1. 비만유도 11
• 2. 조직학적 분석 13
• 1)Modified Mankin score 17
• 2)Glasson score 21
• 3. micro CT 25
• 4.mechanical allodynia 27
• Ⅳ. 고찰 29
• Ⅴ. 결론 34
• 참고문헌 35
• 초록 40