TY - JOUR
T1 - Advanced glycation end products downregulates peroxisome proliferator-activated receptor γ expression in cultured rabbit chondrocyte through MAPK pathway
AU - Yang, Qingshan
AU - Chen, Cheng
AU - Wu, Shujin
AU - Zhang, Ying
AU - Mao, Xinzhan
AU - Wang, Wanchun
PY - 2010/12/15
Y1 - 2010/12/15
N2 - 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.
AB - 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.
KW - Advanced glycation end products
KW - Chondrocyte
KW - Mitogen-activated protein kinases
KW - Peroxisome proliferator-activated receptor γ
UR - http://www.scopus.com/inward/record.url?scp=78049307983&partnerID=8YFLogxK
U2 - 10.1016/j.ejphar.2010.09.025
DO - 10.1016/j.ejphar.2010.09.025
M3 - Article
VL - 649
SP - 108
EP - 114
JO - European Journal of Pharmacology
JF - European Journal of Pharmacology
SN - 0014-2999
IS - 1-3
ER -