PPARγ activation suppresses chondrocyte ferroptosis through mitophagy in osteoarthritis
- J Orthop Surg Res. 2023 Aug 24;18(1):620. doi: 10.1186/s13018-023-04092-x.
- 1. Department of Orthopedics, Guangzhou Red Cross Hospital of Jinan University, Guangzhou, China.
- 2. Guangzhou Institute of Traumatic Surgery, Guangzhou Red Cross Hospital of Jinan University, Guangzhou, China.
- 3. Guizhou Medical University, Guiyang, China.
- 4. Department of Traumatic Orthopedics, The Central Hospital of Xiaogan, Xiaogan, China.
- 5. Guangzhou Institute of Traumatic Surgery, Guangzhou Red Cross Hospital of Jinan University, Guangzhou, China. [email protected].
- 6. Guangzhou Institute of Traumatic Surgery, Guangzhou Red Cross Hospital of Jinan University, Guangzhou, China. [email protected].
- # Contributed equally.
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.