Metformin attenuates osteoarthritis by targeting chondrocytes, synovial macrophages and adipocytes
Metformin attenuates osteoarthritis by targeting chondrocytes, synovial macrophages and adipocytes
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DOI：
10.1093/rheumatology/keac467
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发表时间：
2022-08-19
期刊：
影响因子：
5.5
通讯作者：
Ding, Changhai
中科院分区：
文献类型：
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作者：
Li, Delong;Ruan, Guangfeng;Ding, Changhai
目的探讨二甲双胍对正常饮食(ND)和高脂饮食(HFD)肥胖小鼠膝骨性关节炎的治疗作用及其机制。方法分别对ND小鼠和HFD小鼠进行内侧半月板失稳手术，饮水中或不给予二甲双胍。观察关节结构、滑膜巨噬细胞的浸润和极化以及循环和局部瘦素、脂联素水平的变化。体外实验检测了二甲双胍对软骨细胞和巨噬细胞的作用，以及小鼠腹脂条件培养液对小鼠成软骨细胞系ATDC5和小鼠巨噬细胞系RAW264.7的影响。结果二甲双胍对骨性关节炎有保护作用，治疗10周后OARSI评分[ND鼠2.00，95%CI(1.15，2.86)，HFD鼠3.17，95%CI(2.37，3.96)]和滑膜炎症积分[ND鼠1.17，95%CI(0.27，2.06)，HFD鼠2.50，95%CI(1.49，3.51)]均有降低，且HFD组较ND组更明显。从机制上讲，除了减少软骨细胞的凋亡和基质降解酶的表达以及滑膜巨噬细胞的渗透和促炎分化外，二甲双胍还减少了HFD小鼠脂肪组织的瘦素分泌。结论二甲双胍通过减少软骨细胞的凋亡和分解代谢，抑制滑膜巨噬细胞的侵袭和促炎极化，对膝骨性关节炎有保护作用。对于肥胖小鼠，二甲双胍通过减少脂肪组织中的瘦素分泌，对膝骨性关节炎有更大的保护作用。
Objective To investigate the therapeutic effect and mechanism of metformin on knee OA in normal diet (ND) mice or high-fat diet (HFD)-induced obese mice. Methods Destabilization of the medial meniscus surgery was performed in ND mice or HFD mice, and metformin was administrated in drinking water or not. The changes of OA joint structure, infiltration and polarization of synovial macrophages and circulating and local levels of leptin and adiponectin were evaluated. In vitro, the effects of metformin on chondrocytes and macrophages, and of conditioned mediums derived from mouse abdominal fat on murine chondrogenic cell line ATDC5 and murine macrophage cell line RAW264.7, were detected. Results Metformin showed protective effects on OA, characterized by reductions on OARSI score [2.00, 95% CI (1.15, 2.86) for ND mice and 3.17, 95% CI (2.37, 3.96) for HFD mice] and synovitis score [1.17, 95% CI (0.27, 2.06) for ND mice and 2.50, 95% CI (1.49, 3.51) for HFD mice] after 10 weeks of treatment, and the effects were more significant in HFD mice than in ND mice. Mechanistically, in addition to decreasing apoptosis and matrix-degrading enzymes expression in chondrocytes as well as infiltration and pro-inflammatory differentiation of synovial macrophages, metformin reduced leptin secretion by adipose tissue in HFD mice. Conclusions Metformin protects against knee OA which could be through reducing apoptosis and catabolism of chondrocytes, and suppressing infiltration and pro-inflammatory polarization of synovial macrophages. For obese mice, metformin has a greater protective effect in knee OA additionally through reducing leptin secretion from adipose tissue.