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
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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 (www.letpub.com) 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).
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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