Reactive oxygen species and NADPH oxidase 4 involvement in osteoarthritis

Osteoarthritis (OA) is a degenerative chronic disease affecting > 300,000 million people around the world as of 2016. Symptomatic measures exist, but there are hardly any curative treatments available. Disruption of the cartilage homeostasis in favor of catabolism leads to cartilage destruction. ROS-macromolecular-induced damage is significantly greater in OA cartilage and OA is described as low-grade chronic systemic inflammation. This review aimed to assess the critical role of cartilage ageing and oxidative stress in the OA process, focusing in particular on NADPH oxidase and especially Nox4 involvement. With age, hypertrophic senescent cells with an altered redox cell profile accumulated. Chondrocytes are more sensitive to oxidant-mediators and the serum level of pro-inflammatory mediators increases. Age-related advanced glycation end products impact on extra cellular matrix (ECM) properties leading to the apoptosis of chondrocytes. A focus on NADPH oxidase-mediated-ROS signaling highlighted the very specific Nox4 isoform, which plays a role on the final common pathway targeting chondrocyte cells. IL-1 beta-mediated Nox4 stimulation induced an increase in the levels released by the chondrocyte of MMP-1 and MMP-13 proteins, which are involved in ECM degradation. In comparison with the other Nox isoforms, Nox4 remains unusual, since it is constitutively active, does not depend on cytosolic activator proteins and seems to generate H2O2 thanks to the specific conformation of the Nox4 E-loop. Nox4-induced ROS production appears an essential actor in the OA process and it could be relevant to focus on this target in the aim of discovering and developing new therapeutic strategies.