Glucocorticoids induce apoptosis and matrix metalloproteinase-13 expression in chondrocytes through the NOX4/ROS/p38 MAPK pathway

Based on the results from our previous study, dexamethasone (Dex) increases reactive oxygen species (ROS) levels and subsequently induces cell death and matrix catabolism in chondrocytes. Nevertheless, the mechanism underlying this phenomenon remains unclear. Nicotinamide adenine dinucleotide (phosphate) (NADPH) oxidase 4 (NOX4) is one of the major enzymes responsible for intracellular ROS production during the inflammatory process. The objective of the current study was to investigate the role of NOX4 in Dex-induced ROS over-production. Healthy chondrocytes were harvested from the cartilage debris from 6 female patients. NOX4 and p38 mitogen-activated protein kinase (MAPK) expression levels in these cells were evaluated in the presence of Dex. Changes in the number of apoptotic and viable Dex-treated chondrocytes were recorded after the cells were treated with NOX and p38 MAPK inhibitors. Changes in matrix metalloproteinase 13 (MMP-13) expression levels in Dex-treated chondrocytes were also investigated. The Dex treatment increased NOX4 expression via the glucocorticoid receptor (GR). Treatment of cells with apocynin, a NOX inhibitor, decreased intracellular ROS levels and inhibited p38 MAPK activation. Treatment of cells with a ROS scavenger also reduced p38 MAPK expression. Treatment of cells with a NOX inhibitor, ROS scavenger and p38 MAPK inhibitor rescued chondrocytes from Dex-induced apoptosis. Moreover, treatment of cells with these agents blocked MMP-13 expression in Dex-treated chondrocytes. NOX4 silencing also suppressed p38 MAPK and MMP-13 expression. Dex triggered apoptosis and MMP-13 expression through the NOX4/ROS/p38 MAPK signaling pathway. NOX4 may be a therapeutic target in the management of Dex-induced complications.