Pakistan journal of pharmaceutical sciences · 2026
NOX4 promotes wear particle-stimulated inflammation and osteolysis by ROS-dependent NLRP3 inflammasome activation.
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Xu Changming, Jiang Lei, Da Hu
Аннотация
BACKGROUND: Periprosthetic osteolysis (PIO) induced by wear particles is a major cause of implant failure, yet the underlying molecular mechanisms remain incompletely understood. Oxidative stress and inflammation are key pathological features, but the role of nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) in this process is unclear.
OBJECTIVES: This study aimed to investigate the role and mechanism of NOX4 in wear particle-stimulated inflammation and osteolysis, with a focus on the reactive oxygen species (ROS)/NLRP3 inflammasome signaling pathway.
METHODS: In-vivo and in-vitro PIO models were established using mice and Raw264.7 cells stimulated with cobalt-chromium-molybdenum alloy (Co-Cr-Mo) particles. NOX4 expression, inflammatory factor levels (TNF-α, IL-1β, IL-6), ROS production, and NLRP3 inflammasome activation (NLRP3, ASC, Caspase-1) were examined. The effects of NOX4 silencing, along with NLRP3 and ROS inhibition, were assessed.
RESULTS: Relative to normal mice and control group, the levels of inflammatory factors and NOX4 expression in PIO mice and cobalt-chromium-molybdenum alloy (Co-Cr-Mo)-stimulated Raw264.7 cells were higher. After NOX4 silencing, the levels of inflammatory factors in Raw264.7 cells were lower under situation of Co-Cr-Mo stimulation. The elevated NLRP3 inflammasome activation and ROS level caused by Co-Cr-Mo stimulation were reversed following NOX4 silencing. Co-Cr-Mo elevated the levels of NLRP3, apoptosis-associated speck-like protein containing a CARD (ASC) and Caspase-1 levels, but this effect was reversed after NOX4 silencing. NLRP3 inflammasome inhibitor or ROS inhibitor could reverse the elevated inflammation in Raw264.7 cells under Co-Cr-Mo stimulation.
CONCLUSION: NOX4 promotes wear particle-induced inflammation and osteolysis by activating the ROS-dependent NLRP3 inflammasome, providing new targets for treating periprosthetic osteolysis.
OBJECTIVES: This study aimed to investigate the role and mechanism of NOX4 in wear particle-stimulated inflammation and osteolysis, with a focus on the reactive oxygen species (ROS)/NLRP3 inflammasome signaling pathway.
METHODS: In-vivo and in-vitro PIO models were established using mice and Raw264.7 cells stimulated with cobalt-chromium-molybdenum alloy (Co-Cr-Mo) particles. NOX4 expression, inflammatory factor levels (TNF-α, IL-1β, IL-6), ROS production, and NLRP3 inflammasome activation (NLRP3, ASC, Caspase-1) were examined. The effects of NOX4 silencing, along with NLRP3 and ROS inhibition, were assessed.
RESULTS: Relative to normal mice and control group, the levels of inflammatory factors and NOX4 expression in PIO mice and cobalt-chromium-molybdenum alloy (Co-Cr-Mo)-stimulated Raw264.7 cells were higher. After NOX4 silencing, the levels of inflammatory factors in Raw264.7 cells were lower under situation of Co-Cr-Mo stimulation. The elevated NLRP3 inflammasome activation and ROS level caused by Co-Cr-Mo stimulation were reversed following NOX4 silencing. Co-Cr-Mo elevated the levels of NLRP3, apoptosis-associated speck-like protein containing a CARD (ASC) and Caspase-1 levels, but this effect was reversed after NOX4 silencing. NLRP3 inflammasome inhibitor or ROS inhibitor could reverse the elevated inflammation in Raw264.7 cells under Co-Cr-Mo stimulation.
CONCLUSION: NOX4 promotes wear particle-induced inflammation and osteolysis by activating the ROS-dependent NLRP3 inflammasome, providing new targets for treating periprosthetic osteolysis.