探索二甲双胍作为骨关节炎的新型治疗方法：预防软骨退化和减轻疼痛行为。
Exploration of metformin as novel therapy for osteoarthritis: preventing cartilage degeneration and reducing pain behavior.
机构信息
Department of Orthopaedics, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, 410008, Hunan, China.
Department of Medicine, University of California at San Diego, San Diego, USA.
出版信息
Arthritis Res Ther. 2020 Feb 22;22(1):34. doi: 10.1186/s13075-020-2129-y.
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.
背景
二甲双胍可激活腺苷单磷酸激活的蛋白激酶（AMPK），该激酶被推测为骨关节炎的潜在治疗靶点。本研究旨在观察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 周龄雄性 C57BL/6 小鼠随机分为 6 组：非手术组、假手术组、内侧半月板不稳定（DMM）手术+灌胃生理盐水/二甲双胍组和 DMM 手术+关节内生理盐水/二甲双胍组。通过扫描电子显微镜（SEM）检查关节软骨退变，并采用国际骨关节炎研究协会（OARSI）推荐的评分系统进行评分。通过机械撤足阈值和后爪重量分布测量来评估疼痛相关行为。通过细胞计数试剂盒-8 测定、定量实时聚合酶链反应和 Western blot 分析来检测二甲双胍的合成代谢和抗分解代谢作用，以及 AMPK 在介导其对白细胞介素-1β刺激的原代小鼠软骨细胞的作用。
结果
与灌胃和关节内生理盐水组相比，灌胃和关节内二甲双胍组的小鼠关节软骨退变明显减轻，SEM 下软骨损伤程度较轻，OARSI 评分明显较低。与 DMM 模型的相应生理盐水组相比，灌胃和关节内二甲双胍组的小鼠撤足阈值较高，负重不对称性降低。体外实验表明，二甲双胍通过激活 AMPK 通路，不仅降低了基质金属蛋白酶 13 的水平，而且增加了 II 型胶原的产生。
结论
二甲双胍可减轻骨关节炎结构恶化并调节疼痛，表明其在骨关节炎预防或治疗方面具有潜力。
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