Baicalin inhibits IL-1ß-induced ferroptosis in human osteoarthritis chondrocytes by activating Nrf-2 signaling pathway.

BACKGROUND: Osteoarthritis (OA) is a common degenerative disease involving articular cartilage, in which ferroptosis of chondrocytes plays an important role. Baicalin (BAI) exerts regulatory effects in a wide range of orthopedic diseases including OA, but its effect on ferroptosis of chondrocytes (CHs) is still unclear. The purpose of this study was to determine the effect of BAI on ferroptosis in human OA chondrocytes (OACs), and to explore its possible mechanism. METHODS: CHs were treated with IL-1ß (10 ng/mL) to simulate inflammation in vitro. Immunofluorescence, quantitative RT-PCR, Western blotting and cell viability assay were performed to evaluate the impacts of BAI on Fe2+ level, mitochondrial dysfunction, ferroptosis-related proteins, oxidative stress and cytotoxicity in CHs. Additionally, siRNA was made use of to knock out nuclear factor E2-related factor 2 (Nrf2) to analyze the role played by Nrf2 in BAI-induced CH ferroptosis. RESULTS: BAI eliminated IL-1ß-induced Fe2+ accumulation, changes in mitochondrial membrane potential and ferroptosis-related protein GPX4, SLC7A11, P53 and ACSL4 levels, as well as reactive oxygen species (ROS), lipid peroxidation (LPO) and malondialdehyde (MDA) accumulation in CHs. Besides, BAI reversed IL-1ß-induced decrease of Collagen II and increase of MMP13 in CHs. Meanwhile, BAI attenuated IL-1ß-induced CH toxicity and promoted Nrf2 antioxidant system activation. When Nrf2 was knocked down by siRNA, the effects of BAI on IL-1ß-induced ferroptosis-related proteins and antioxidant stress in CHs were significantly weakened. CONCLUSIONS: This study demonstrates that IL-1ß can induce CH ferroptosis. BAI is able to inhibit IL-1ß-induced CH ferroptosis and ECM degradation, and the specific mechanism may be that it can inhibit IL-1ß-induced CH ferroptosis by activating Nrf2 antioxidant system to attenuate the accumulation of intracellular ROS and lipid ROS.

Trelagliptin ameliorates IL-1ß-impaired chondrocyte function via the AMPK/SOX-9 pathway.

Chondrocyte dysregulation plays a critical role in the development of osteoarthritis (OA). The pro-inflammatory cytokine interleukin-1ß (IL-1ß) activates chondrocytes and degrades the structural extracellular matrix (ECM). These events are the important mechanism of OA. Trelagliptin, a selective inhibitor of dipeptidyl Peptidase 4 (DPP-4) used for the treatment of type 2 diabetes mellitus (T2DM), has displayed a wide range of anti-inflammatory capacities. The effects of Trelagliptin in OA and chondrocytes have not been tested before. Here, we show that Trelagliptin mitigates IL-1ß-induced production of inflammatory cytokines such as interleukin 6 (IL-6), interleukin 8 (IL-8), and tumor necrosis factor-alpha (TNF-α) in human chondrocytes. Trelagliptin ameliorates IL-1ß-induced oxidative stress by reducing the generation of reactive oxygen species (ROS). Particularly, the presence of Trelagliptin prevents IL-1ß-induced reduction of Acan genes and the protein Aggrecan. Moreover, we show that Trelagliptin restores IL-1ß-induced reduction of SOX-9 and that the knockdown of SOX-9 abolishes the protective effects of Trelagliptin. Mechanistically, we demonstrate that AMPK is required for the amelioration of Trelagliptin on SOX-9- reduction by IL-1ß. Collectively, our study demonstrates that the DPP-4 inhibitor Trelagliptin has a protective effect on chondrocyte function. Trelagliptin may have the potential role to antagonize chondrocyte-derived inflammation in OA.