BACKGROUND Metformin could activate adenosine monophosphate-activated protein kinase (AMPK) which was postulated as a potential therapeutic target for osteoarthritis. This study aimed to examine the effects of metformin on cartilage and pain in osteoarthritis mouse model. METHODS Eighty 10-week-old male C57BL/6 mice were randomized to 6 groups: non-operation, sham-operation, destabilization of the medial meniscus (DMM)-operation with intragastric saline/metformin, and DMM-operation with intraarticular saline/metformin. Articular cartilage degeneration was examined by scanning electron microscopy (SEM) and graded using the scoring system recommended by Osteoarthritis Research Society International (OARSI). Mechanical withdrawal threshold and hind paw weight distribution were measured to assess the pain-related behavior. Cell Counting Kit-8 assay, quantificational real-time polymerase chain reaction, and western blot analysis were conducted to examine the anabolic and anti-catabolic effect of metformin and the role of AMPK in mediating its effects on interleukin-1β stimulated primary mice chondrocytes. RESULTS Compared with mice receiving intragastric and intraarticular saline, mice in both intragastric and intraarticular metformin displayed attenuated articular cartilage degeneration, indicated by less cartilage damage under SEM and significantly lower OARSI scores. A higher paw withdrawal threshold and a decreased weight-bearing asymmetry were observed in the intragastric and intraarticular metformin mice compared with their corresponding saline groups in DMM model of osteoarthritis. In vitro experiments showed that metformin not only decreased the level of matrix metalloproteinase 13, but also elevated type II collagen production through activating AMPK pathway. CONCLUSIONS Metformin attenuates osteoarthritis structural worsening and modulates pain, suggesting its potential for osteoarthritis prevention or treatment.

中文翻译：

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探索二甲双胍作为骨关节炎的新疗法：预防软骨变性和减少疼痛行为。

背景技术二甲双胍可以激活被认为是骨关节炎的潜在治疗靶标的腺苷单磷酸激活蛋白激酶（AMPK）。这项研究旨在检查二甲双胍对骨关节炎小鼠模型软骨和疼痛的影响。方法将80只10周大的雄性C57BL / 6小鼠随机分为6组：非手术，假手术，内侧半月板失稳（DMM）手术，胃内注射生理盐水/二甲双胍和DMM手术，关节内注射生理盐水/二甲双胍。通过扫描电子显微镜（SEM）检查关节软骨的退变，并使用国际骨关节炎研究协会（OARSI）推荐的评分系统进行评分。测量机械退缩阈值和后爪重量分布，以评估疼痛相关行为。Cell Counting Kit-8检测，进行实时定量聚合酶链反应定量和蛋白质印迹分析，以检查二甲双胍的合成代谢和抗分解代谢作用以及AMPK在介导白介素1β刺激的原代小鼠软骨细胞中的作用。结果与接受胃内和关节内生理盐水的小鼠相比，处于胃内和关节内二甲双胍的小鼠均表现出减弱的关节软骨变性，这表明在SEM下软骨损伤较少，并且OARSI评分明显较低。与骨关节炎DMM模型中相应的生理盐水组相比，胃内和关节内二甲双胍小鼠的爪退缩阈值更高，负重不对称性降低。体外实验表明，二甲双胍不仅降低了基质金属蛋白酶13的水平，而且还可以通过激活AMPK途径提高II型胶原蛋白的产量。结论二甲双胍减轻了骨关节炎的结构恶化并调节了疼痛，表明其具有预防或治疗骨关节炎的潜力。