title: Advanced glycation end products downregulates peroxisome proliferator-activated receptor γ expression in cultured rabbit chondrocyte through MAPK pathway.
abstract: Accumulation of advanced glycation end products (AGEs) which are known to adversely affect cartilage turnover and mechanical properties, provides a molecular mechanism by which aging contributes to the development of osteoarthritis. The objective of the present study was to investigate the role of peroxisome proliferator-activated receptor γ (PPARγ) in AGEs-mediated chondrocytes damage. In the cultured rabbit chondrocytes, our results show that the PPARγ agonist pioglitazone can concentration-dependently inhibit the AGEs-induced expression of TNF-α and MMP-13. Several studies have shown that activation of PPARγ may interfere with several signaling pathways regulating the proinflammatory genes in vivo and vitro experiments, but little is known regarding their expression and regulation in cartilage. Thus the effect of AGEs on PPARγ expression was next examined. Reverse transcription (RT)-PCR analysis revealed that AGEs treatment of chondrocytes downregulated PPARγ expression in a time- and concentration-dependent manner. AGEs-induced a significant downregulation in PPARγ mRNA at 48 h and the maximum effect was found at 100 μg/ml AGEs. This effect was significantly depressed by the anti-RAGE antibody. Specific inhibitors of the mitogen-activated protein kinases (MAPK) p38 (SB203580) and c-Jun N-terminal kinase (SP600125), but not of extracellular signal-regulated kinase (PD98059), prevented AGEs-induced downregulation of PPARγ expression. In conclusion, AGEs may be responsible for PPARγ downregulation via a mechanism involving activation of the MAPK (p38 and JNK), and this downregulation might play a key role in AGEs-induced production of TNF-α and MMP-13.
authors.affiliation: Department of Orthopaedics, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China.
authors.forename: Qingshan
authors.initials: Q
authors.lastname: Yang
authors.forename: Cheng
authors.initials: C
authors.lastname: Chen
authors.forename: Shujin
authors.initials: S
authors.lastname: Wu
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.forename: Xinzhan
authors.initials: X
authors.lastname: Mao
authors.forename: Wanchun
authors.initials: W
authors.lastname: Wang
mesh_terms: D000818:Animals; D002358:Cartilage, Articular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D019902:Chondrocytes / Q000187:drug effects / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D017127:Glycation End Products, Advanced / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D053509:Matrix Metalloproteinase 13 / Q000235:genetics / Q000378:metabolism*; D010003:Osteoarthritis / Q000503:physiopathology; D047495:PPAR gamma / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D000077205:Pioglitazone; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D011817:Rabbits; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012710:Serum Albumin, Bovine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D045162:Thiazolidinediones / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*
chemical_list: D017127:Glycation End Products, Advanced; D047495:PPAR gamma; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D045162:Thiazolidinediones; D014409:Tumor Necrosis Factor-alpha; C081628:advanced glycation end products-bovine serum albumin; D012710:Serum Albumin, Bovine; D053509:Matrix Metalloproteinase 13; D000077205:Pioglitazone