Astaxanthin attenuates osteoarthritis progression via inhibiting ferroptosis and regulating mitochondrial function in chondrocytes

Abstract

Ferroptosis is a novel form of regulated cell death that has a close association with mitochondrial dysfunction and is characterized by iron overload, the accumulation of reactive oxygen species (ROS), and lipid ROS. Chondrocytes ferroptosis accelerates the progression of osteoarthritis (OA). Astaxanthin (ATX) is a xanthophyll carotenoid that possesses anti-inflammatory and antioxidant properties and has been explored in research studies for the treatment of diabetes and cardiovascular disease. However, the role it plays in OA, particularly in chondrocyte ferroptosis, has not yet been reported. In this study, ferroptosis-related events were analyzed in rat chondrocytes in vitro. A surgical destabilized medial meniscus was performed for the establishment of in vivo OA model. The results showed that interleukin-1β (IL-1β) induced inflammatory injury in chondrocytes through the promotion of the expressions of inflammatory factors including inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX2). IL-1β triggered chondrocyte ferroptosis by increasing the levels of intracellular ROS, lipid ROS, iron, and mitochondrial iron and inhibiting the expressions of SLC7A11/glutathione peroxidase 4 (GPX4) and Ferritin. The above indices were ameliorated by ferrostatin-1 (Fer-1, a classic ferroptosis inhibitor) and ATX. Furthermore, Fer-1 and ATX rescued the IL-1β-induced down-regulating collagen type II (collagen Ⅱ) and up-regulating matrix metalloproteinase 13 (MMP13). Following treatment with IL-1β, mitochondrial membrane potential decreased and the mitochondrial membrane was broken. At the same time, the mitochondrion shrank, becoming deformed as the mitochondrial cristae reduced and became disrupted. These changes were entirely consistent with ferroptosis features. All the aforementioned phenomena were reversed by Fer-1 and ATX. In addition, intra-articular injection of Fer-1 and ATX delayed articular cartilage degradation and OA progression. This study demonstrated that IL-1β can induce inflammatory damage and ferroptosis in chondrocytes. Both Fer-1 and ATX have the ability to mitigate chondrocyte injury and osteoarthritis progression by inhibiting ferroptosis and the regulation of mitochondrial function. Targeting ferroptosis has the potential to be a promising future treatment method for OA.

Keywords: Astaxanthin; Ferroptosis; GPX4; Mitochondrion; Osteoarthritis; SLC7A11.