Research Paper Volume 12, Issue 6 pp 5152—5167
Rapamycin protects chondrocytes against IL-18-induced apoptosis and ameliorates rat osteoarthritis
- 1 Department of Orthopedic Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310000, Zhejiang, China
received: November 2, 2019 ; accepted: January 27, 2020 ; published: March 17, 2020 ;https://doi.org/10.18632/aging.102937
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Copyright © 2020 Bao et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Interleukin 18 (IL-18) promotes inflammation and apoptosis in chondrocytes, thereby contributing to the development and progression of osteoarthritis (OA). Here, we investigated the effects of IL-18 treatment and inhibition in rat chondrocytes in vitro and in vivo. We used RT-PCR and Western blotting to measure the mRNA and protein levels of the chondrocyte-specific genes Collagen II and Aggrecan as well as the protein levels of apoptosis-related (Bax, Bcl2, Caspase3/9), autophagy-related (Atg5, Atg7, Beclin1, LC3), and mTOR pathway-related genes (PI3K, Akt, mTOR). We observed a decrease in Collagen II and Aggrecan mRNA and protein levels, upregulation of chondrocyte apoptosis, downregulation of chondrocyte autophagy, and activation of the PI3K/Akt/mTOR pathway upon IL-18 treatment. PI3K/Akt/mTOR pathway activation and inhibition tests using rat 740Y-P (PI3K activator), SC79 (AKT activator), 3BDO (mTOR activator), or LY294002 (PI3K inhibitor) revealed that activation of the PI3K/Akt/mTOR pathway enhances chondrocyte-specific gene degradation induced by IL-18, while its inhibition has protective effects on chondrocytes. We also found that treatment with rapamycin (a selective mTOR inhibitor) also exerts chondro-protective effects that ameliorate OA by promoting autophagy. These results suggest that inhibition of the mTOR pathway could be exploited for therapeutic benefits in the treatment of OA.
IL-18: Interleukin 18; OA: Osteoarthritis; mTOR: Mammalian target of rapamycin; Rapa: Rapamycin; Bcl2: B-cell leukemia/lymphoma 2; BAX: Bcl2-associated X; Atg5: Autophagy-related protein 5; Atg7: Autophagy-related protein 7; LC3: Microtubule-associated protein 1 light chain 3; PI3K: Phosphatidylinositol 3-kinase; Ab: Antibodies.