PPARγ activation suppresses chondrocyte ferroptosis through mitophagy in osteoarthritis

Author:

Xue Xiang,Dai Tianming,Chen Junyan,Xu Yangyang,Yang Zhenyu,Huang Jian,Xu Wuyan,Li Siming,Meng Qingqi

Abstract

Abstract Background Osteoarthritis (OA) is a prevalent disease plaguing the elderly. Recently, chondrocyte ferroptosis has been demonstrated to promote the progression of OA. Peroxisome proliferator-activated receptor-γ (PPARγ) is an important factor in maintaining cartilage health. However, the relationship between PPARγ and chondrocyte ferroptosis in OA and its mechanism is completely unclear. Methods We established a surgically induced knee OA rat model to investigate PPARγ and chondrocyte ferroptosis in OA. Rat knee specimens were collected for Safranin O/Fast Green staining and immunohistochemical staining after administered orally placebo or pioglitazone (PPARγ agonist) for 4 weeks. We used RSL3 to establish a chondrocyte ferroptosis model cultured in vitro to study the role of PPARγ activation toward ferroptosis, mitochondrial function, and PTEN-induced putative kinase 1 (Pink1)/Parkin-dependent mitophagy. GW9662 (PPARγ antagonist), Mdivi-1 (mitophagy inhibitor), and chloroquine (mitophagy inhibitor) were employed to investigate the mechanism of PPARγ-Pink1/Parkin-dependent mitophagy in the inhibition of ferroptosis. Results We found that PPARγ activation by pioglitazone attenuated not only OA but also inhibited the expression of the ferroptosis marker acyl-CoA synthetase long-chain family member 4 (ACSL4) at the same time in rats. Furthermore, in vivo and in vitro data indicated that PPARγ activation restored Pink1/Parkin-dependent mitophagy, improved mitochondrial function, inhibited chondrocyte ferroptosis, and delayed the progression of OA. Conclusions The present study demonstrated that PPARγ activation attenuates OA by inhibiting chondrocyte ferroptosis, and this chondroprotective effect was achieved by promoting the Pink1/Parkin-dependent mitophagy pathway.

Funder

Guangdong Provincial Natural Science Foundation

Science and Technology Program of Guangzhou

Publisher

Springer Science and Business Media LLC

Subject

Orthopedics and Sports Medicine,Surgery

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1. The Role of Ferroptosis in Osteoarthritis: Progress and Prospects;Biochemical and Biophysical Research Communications;2024-09

2. METTL3 mediated ferroptosis in chondrocytes and promoted pain in KOA via HMGB1 m6A modification;Cell Biology International;2024-08-11

3. Ferroptosis in Arthritis: Driver of the Disease or Therapeutic Option?;International Journal of Molecular Sciences;2024-07-27

4. Function and Mechanism of Abscisic Acid on Microglia-Induced Neuroinflammation in Parkinson’s Disease;International Journal of Molecular Sciences;2024-04-30

5. The dysregulated autophagy in osteoarthritis: Revisiting molecular profile;Progress in Biophysics and Molecular Biology;2024-03

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