Apoptosis

, Volume 21, Issue 10, pp 1082–1093

Pioglitazone inhibits advanced glycation end product-induced matrix metalloproteinases and apoptosis by suppressing the activation of MAPK and NF-κB

  • Hai-Bin Zhang
  • Ying Zhang
  • Cheng Chen
  • Yu-Qing Li
  • Chi Ma
  • Zhao-Jun Wang
Article

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.

Keywords

Advanced glycation end products Osteoarthritis Pioglitazone Apoptosis Cartilage degeneration Matrix metalloproteinases Mitogen-activated protein kinases NF-κB 

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Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Hai-Bin Zhang
    • 1
  • Ying Zhang
    • 1
  • Cheng Chen
    • 1
  • Yu-Qing Li
    • 1
  • Chi Ma
    • 2
  • Zhao-Jun Wang
    • 1
  1. 1.Department of Orthopedics, The 163rd Central Hospital of the People’s Liberation ArmyThe Second Affiliated Hospital of Hunan Normal UniversityChangshaPeople’s Republic of China
  2. 2.Department of OrthopedicsPeople’s Hospital of Xiangxi Autonomous PrefectureJishouChina

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