Inhibition of NADPH Oxidases Prevents the Development of Osteoarthritis

Increased oxidative stress in osteoarthritis (OA) cartilage mediates catabolic signal transduction leading to extracellular matrix degradation and chondrocyte apoptosis. This study aimed to explore the contribution of NADPH oxidase (NOX), a major source of cellular reactive oxygen species (ROS), to the catabolic process of chondrocytes and to OA. The inhibition of NOX isoforms with a pan-NOX inhibitor, APX-115, significantly decreased IL-1 beta-induced ROS production in primary chondrocytes and, most potently, suppressed the expression of oxidative stress marker genes and catabolic proteases compared with the inhibition of other ROS sources. Catabolic stimuli by IL-1 beta treatment and in post-traumatic OA conditions upregulated the expression of NOX2 and NOX4 in chondrocytes. In the post-traumatic OA model, the pharmacologic inhibition of NOX protected mice against OA by modulating the oxidative stress and the expression of MMP-13 and Adamts5 in chondrocytes. Mechanistically, NOX inhibition suppresses Rac1, p38, and JNK MAPK signaling consistently and restores oxidative phosphorylation in IL-1 beta-treated chondrocytes. In conclusion, NOX inhibition prevented the development of OA by attenuating the catabolic signaling and restoring the mitochondrial metabolism and can thus be a promising class of drug for OA.

Automated summary

Increased oxidative stress in OA cartilage leads to extracellular matrix degradation and chondrocyte apoptosis. This study found that inhibiting NOX can decrease ROS production, suppress oxidative stress marker genes and catabolic proteases, and protect against OA by modulating oxidative stress and gene expression.