, Volume 21, Issue 10, pp 1082–1093 | Cite as

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


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.


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



The authors wish to thank the Animal Experiment Center of Medicine School of Hunan Normal University, for the animal care, technical and logistical support. We would also like to thank all the institutions for their financial support. We thank LetPub ( for its linguistic assistance during the preparation of this manuscript.

Role of the funding source

The study was supported by National Natural Science Foundation of China (NO. 81201432), Army Medical Research Subject of the “12th Five-Year-Plan” (NO. CWS11J275), Scientific Research Fund of Hunan Provincial Education Department (NO.15B140), and Hunan Provincial Innovation Foundation for Postgraduate (NO.CX2015B185).

Author contributions

All authors have made substantial contributions to this study. Haibin Zhang contributed to study design, data collection, analysis and interpretation of the data, drafting of the manuscript, and final approval of the article. Ying Zhang contributed to study design, interpretation of the data, drafting and critical revision of the article for important intellectual content, and final approval of the article. Cheng Chen provided the study materials, contributed to critical revision of the article for important intellectual content, and final approval of the article. Yuqing Li, Chi Ma and Zhaojun Wang contributed to study design, critical revision of the article for important intellectual content, and final approval of the article.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.


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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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