Nox4 mediates chondrocyte senescence and cartilage degradation in post-traumatic osteoarthritis via the ROS/p38MAPK signaling pathway

Osteoarthritis (OA) is a degenerative joint disease characterized by cartilage degradation and chondrocyte senescence. Emerging evidence implicates NADPH oxidase 4 (Nox4) in OA pathogenesis. This study investigated the role of Nox4 in regulating extracellular matrix (ECM) homeostasis and chondrocyte senescence through the p38 mitogen-activated protein kinase (p38MAPK) signaling pathway. We found that Nox4 expression was significantly upregulated in OA chondrocytes and cartilage. In a post-traumatic OA mouse model (Anterior cruciate ligament transection, ACLT), Nox4 knockout attenuated cartilage damage and chondrocyte senescence, while preserving ECM proteins such as type II collagen and aggrecan. In vitro experiments further demonstrated that Nox4 overexpression accelerated chondrocyte senescence, impaired ECM synthesis, and upregulated senescence markers (p16, p21, p53). Conversely, pharmacological inhibition of Nox4 with GKT137831 or scavenging reactive oxygen species (ROS) with N-acetylcysteine (NAC) alleviated these effects, suggesting that Nox4 contributes to chondrocyte senescence potentially via ROS accumulation. Furthermore, Nox4-induced p38MAPK activation was closely associated with increased senescence and ECM degradation, and these pathological changes were reversed by the p38MAPK inhibitor SB203580. These findings highlight the Nox4-p38MAPK axis as acritical driver of OA progression and suggest that targeting this pathway may offer a promising therapeutic strategy to mitigate cartilage degradation and senescence.