文献类型：期刊文献

中文题名：糖基化终末产物通过下调AMPK/PGC-1α/SIRT3信号通路诱导软骨细胞线粒体功能损伤

英文题名：Advanced glycation end products induces mitochondrial dysfunction via downregulating AMPK/PGC-1α/SIRT3 signaling pathway in chondrocytes

作者：史宇悰[1,2,3];李文竟[1,3];杨宇航[1,3];黄子炎[1,3];廖习武[1,3];王刚[4];石磊[5];杨青山[1,3]

第一作者：史宇悰

机构：[1]甘肃省人民医院骨科,甘肃兰州730000;[2]首都医科大学附属北京积水潭医院急诊科,北京102208;[3]甘肃中医药大学第一临床医学院,甘肃兰州730000;[4]高台县中医院骨科,甘肃张掖734300;[5]甘肃省人民医院药剂科,甘肃兰州730000

第一机构：甘肃省人民医院骨科,甘肃兰州730000

年份：2026

卷号：42

期号：1

起止页码：94

中文期刊名：中国药理学通报

外文期刊名：Chinese Pharmacological Bulletin

收录：;北大核心:【北大核心2023】；

基金：国家自然科学基金资助项目(No 82060409,82460427);甘肃省自然科学基金资助项目(No 24JRRA587)。

语种：中文

中文关键词：糖基化终末产物;线粒体功能损伤;骨性关节炎;AMPK;PGC-1α;SIRT3

外文关键词：advanced glycation end products;mitochondrial dysfunction;osteoarthritis;AMPK;PGC-1α;SIRT3

摘要：目的通过动物和体外培养的软骨细胞观察糖基化终末产物(advanced glycation end products,AGEs)对软骨细胞线粒体功能的损伤作用,并探讨相关机制。方法小鼠膝关节腔直接注射AGEs,番红O-固绿染色评估病理学改变;JC-1检测线粒体膜电位ΔΨm;Western blot检测腺苷酸活化蛋白激酶(adenosine monophosphate-activated protein kinase,AMPK)、过氧化物酶体增殖物激活受体γ辅助活化因子α(peroxisome proliferator-activated receptorγcoactivator-1α,PGC-1α)、去乙酰化酶3(sirtuin3,SIRT3)及基质金属蛋白酶(matrix metalloproteinase,MMP)-3、-13的表达。结果膝关节注射AGEs 8周后,小鼠出现骨关节炎样病理改变;在体外培养的软骨细胞中,AGEs可以损伤线粒体功能,同时p-AMPK、SIRT3和PGC-1α的表达减少;给予AMPK选择性激动剂AICAR则可以拮抗AGEs的上述作用,而特异性敲除SIRT3或PGC-1α后,AICAR此拮抗作用减弱。结论AGEs可能通过下调AMPK-PGC-1α-SIRT3信号通路诱导软骨细胞线粒体功能损伤,进而促进OA病变。
Aim To investigate the impact of advanced glycation end products(AGEs)on mitochondrial function in both animal model and chondrocytes,and to explore whether these effects are mediated through the inhibition of the AMPK/PGC-1α/SIRT3 signaling pathway.Methods AGEs were administered via intra-articular injection in mice.Osteoarthritis-like lesions in knee joints were assessed using safranin Ofast green staining.Mitochondrial membrane potential(ΔΨm)was evaluated using the JC-1 assay.The expression levels of adenosine monophosphate-activated protein kinase(AMPK),peroxisome proliferatoractivated receptorγcoactivator-1α(PGC-1α),sirtuin 3(SIRT3),matrix metalloproteinase(MMP)-3,and MMP-13 were measured by Western blot.Results Intra-articular injection of AGEs induced osteoarthritislike pathological changes in mice after 8 weeks.AGEs significantly impaired mitochondrial function,accompanied by reduced phosphorylation of AMPK and decreased expression of SIRT3 and PGC-1α.Treatment with the selective AMPK agonist AICAR mitigated AGEs-induced mitochondrial damage;however,these protective effects were abolished in SIRT3-knockout or PGC-1α-knockout chondrocytes.Conclusions AGEs induce mitochondrial dysfunction in chondrocytes by downregulating the AMPK-PGC-1α-SIRT3 signaling pathway,thereby promoting the progression of osteoarthritis.