Objective: Osteoarthritis (OA) is a prevalent joint disease featured by articular cartilage destruction, causing a huge socio-economic burden worldwide. Repressing endoplasmic reticulum stress (ERS)-mediated ferroptosis can alleviate the progression of OA. Sirtuin 6 (SIRT6) has been shown to suppress OA, but whether SIRT6 can regulate ferroptosis in OA through ERS remains unclear.
Methods: In this study, both in vivo and in vitro models of OA were constructed. Micro-CT scans and three-dimensional reconstruction were used to observe the structural injury of knee joint in mice. H&E, TB, SOFG and TUNEL staining were employed to conduct pathological examination of cartilage tissues. The levels of inflammatory factors were analyzed using ELISA. Besides, ERS was assessed by detecting the levels of ERS-related proteins using immunohistochemistry, immunoblotting and immunofluorescence staining. Iron deposition in cartilage tissues was tested by prussian blue staining. Moreover, the contents of intracellular ROS, lipid ROS and Fe were evaluated in IL-1β-stimulated C28/I2 cells. Finally, ML385 (an inhibitor of Nrf2) or tunicamycin (an agonist of ERS) was added to C28/I2 cells to elucidate the exact mechanism.
Results: SIRT6 upregulation reduced the structural injury and inflammation in cartilage tissues of OA mice. ERS and ferroptosis were inhibited by SIRT6 overexpression in cartilage tissues of OA mice and C28/I2 cells exposed to IL-1β. Additionally, SIRT6 upregulation activated Nrf2/HO-1 signaling, as evidenced by elevated nuclear Nrf2 and HO-1 expression. Further, ML385 treatment attenuated the impacts of SIRT6 overexpression on inflammation, ERS and ferroptosis in C28/I2 cells under IL-1β conditions. Particularly, tunicamycin intervention blocked the effects of SIRT6 upregulation on ferroptosis in IL-1β-treated C28/I2 cells.
Conclusions: Collectively, SIRT6 inhibits ERS-medicated ferroptosis through activation of Nrf2/HO-1 pathway in chondrocytes to alleviate OA.
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