Interleukin-1β-induced arthritis involves chondrocyte oxiapoptophagy

Pro-inflammatory cytokine-induced chondrocyte death contributes to various types of arthritis, including osteoarthritis and rheumatoid arthritis. Recent studies have indicated that oxysterols induce oxiapoptophagy, a form of cell death characterized by oxidative stress, apoptosis, and autophagy. This study aimed to determine whether interleukin-1β (IL-1β)-induced articular cartilage degeneration is associated with chondrocyte oxiapoptophagy. Intra-articular injection of IL-1β into the knee joints of experimental animals induced progressive articular cartilage degeneration and promoted the expression of cholesterol-25-hydroxylase (CH25H), 25-hydroxycholesterol 7α-hydroxylase (CYP7B1), caspase-3, cyclooxygenase-2 (COX-2), and beclin-1. Consistently, IL-1β-stimulated cartilage explants showed proteoglycan loss, and chondrocytes exhibited increased expression and activation of matrix metalloproteinases (MMP-1, MMP-3, MMP-13). IL-1β upregulated the expression of CH25H and CYP7B1, thereby increasing 25-HC production in chondrocytes. Sequentially, IL-1β promoted chondrocyte apoptosis by triggering the caspase cascade, while levels of oxidative stress-related molecules, including reactive oxygen species (ROS), inducible nitric oxide synthase, COX-2, nitric oxide, and prostaglandin E₂, were elevated in chondrocytes. Additionally, IL-1β increased autophagosome formation and the expression of autophagy biomarkers, including beclin-1 and microtubule-associated protein 1A/1B-light chain 3, by increasing p53 and decreasing the phosphorylation of Akt and mTOR in chondrocytes. Furthermore, IL-1β increased the phosphorylation of NF-κB, which subsequently translocated from the cytosol to the nucleus in chondrocytes. CDDO-Me, an inhibitor of the NF-κB pathway, suppressed the IL-1β-induced expression of CH25H, CYP7B1, caspase-3, and beclin-1, as well as ROS production in chondrocytes. Collectively, these findings consistently indicate that IL-1β-induced articular cartilage degeneration is associated with chondrocyte oxiapoptophagy via the NF-κB signaling pathway.