title: Pioglitazone inhibits advanced glycation end product-induced matrix metalloproteinases and apoptosis by suppressing the activation of MAPK and NF-κB.
abstract: Apoptosis and degeneration coming mainly from chondrocytes are important mechanisms in the onset and progression of osteoarthritis. Specifically, advanced glycation end products (AGEs) play an important role in the pathogenesis of osteoarthritis. Pioglitazone, a peroxisome proliferator-activated receptor γ (PPARγ) agonist has a protective effect on cartilage. This study aims to evaluate the effect of pioglitazone on AGEs-induced chondrocyte apoptosis and degeneration and their underlying mechanism. The in vitro study shows that AGEs induce cleavage of caspase-3 and PARP, up-regulate MMP-13 expression, enhance chondrocyte apoptosis and down-regulate PPARγ expression in human primary chondrocytes, which is reversed by pioglitazone. Furthermore, AGEs activate phosphorylation of Erk, JNK, and p38, and pioglitazone reverses AGEs-induced phosphorylation of Erk and p38. AGEs-induced degradation of IκBα and translocation of nuclear NF-κB p65 is reversed by pioglitazone. Pretreatment of chondrocytes with SB202190 (p38 inhibitor), SP600125 (JNK inhibitor) and BAY-11-7082 (NF-κB inhibitor) inhibit AGEs-induced apoptosis and degeneration. In vivo experiments suggest that pioglitazone reverses AGEs-induced cartilage degeneration and apoptosis in a mouse model, as demonstrated by HE and Safranin O staining, immunohistochemical analyses of Type II collagen (Col II), metalloproteinases (MMPs) and caspase-3. These findings suggest that pioglitazone, a PPARγ agonist, inhibits AGEs-induced chondrocytes apoptosis and degeneration via suppressing the activation of MAPK and NF-κB.
authors: Department of Orthopedics, The 163rd Central Hospital of the People's Liberation Army, The Second Affiliated Hospital of Hunan Normal University, Changsha, 410003, Hunan, People's Republic of China.
authors: Hai-Bin
authors: HB
authors: Zhang
authors: Department of Orthopedics, The 163rd Central Hospital of the People's Liberation Army, The Second Affiliated Hospital of Hunan Normal University, Changsha, 410003, Hunan, People's Republic of China.
authors: Ying
authors: Y
authors: Zhang
authors: Department of Orthopedics, The 163rd Central Hospital of the People's Liberation Army, The Second Affiliated Hospital of Hunan Normal University, Changsha, 410003, Hunan, People's Republic of China. hnzhanghaibin@163.com.
authors: Cheng
authors: C
authors: Chen
authors: Department of Orthopedics, The 163rd Central Hospital of the People's Liberation Army, The Second Affiliated Hospital of Hunan Normal University, Changsha, 410003, Hunan, People's Republic of China.
authors: Yu-Qing
authors: YQ
authors: Li
authors: Department of Orthopedics, People's Hospital of Xiangxi Autonomous Prefecture, Jishou, Hunan, China.
authors: Chi
authors: C
authors: Ma
authors: Department of Orthopedics, The 163rd Central Hospital of the People's Liberation Army, The Second Affiliated Hospital of Hunan Normal University, Changsha, 410003, Hunan, People's Republic of China.
authors: Zhao-Jun
authors: ZJ
authors: Wang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism*; D019902:Chondrocytes / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D053509:Matrix Metalloproteinase 13 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D010003:Osteoarthritis / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism / Q000503:physiopathology; D010766:Phosphorylation; D000077205:Pioglitazone; D045162:Thiazolidinediones / Q000008:administration & dosage*; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism
chemical_list: D017127:Glycation End Products, Advanced; D016328:NF-kappa B; D045162:Thiazolidinediones; D051996:Transcription Factor RelA; D053148:Caspase 3; D053509:Matrix Metalloproteinase 13; D000077205:Pioglitazone
keywords: Advanced glycation end products; Apoptosis; Cartilage degeneration; Matrix metalloproteinases; Mitogen-activated protein kinases; NF-κB; Osteoarthritis; Pioglitazone