biostudies-literatureArra MNIAMS NIH HHSU.S. Department of Health & Human Services | National Institutes of HealthShriners Hospitals for Children3427https://www.ebi.ac.uk/biostudies/studies/S-EPMC7347613biostudies-literatureUnknown11(1)The contribution of inflammation to the chronic joint disease osteoarthritis (OA) is unclear, and this lack of clarity is detrimental to efforts to identify therapeutic targets. Here we show that chondrocytes under inflammatory conditions undergo a metabolic shift that is regulated by NF-κB activation, leading to reprogramming of cell metabolism towards glycolysis and lactate dehydrogenase A (LDHA). Inflammation and metabolism can reciprocally modulate each other to regulate cartilage degradation. LDHA binds to NADH and promotes reactive oxygen species (ROS) to induce catabolic changes through stabilization of IκB-ζ, a critical pro-inflammatory mediator in chondrocytes. IκB-ζ is regulated bi-modally at the stages of transcription and protein degradation. Overall, this work highlights the fNature communicationsLDHA-mediated ROS generation in chondrocytes is a potential therapeutic target for osteoarthritis.PMC7347613R01 AR04919285160AR075860AR057235R01 AR068972R01 AR064755AR049192AR054326AR072623P30 AR074992AR068972P30 AR057235R01 AR075860R01 AR054326R01 AR072623AR064755Shen JSwarnkar GKe KYing JArra MRai MFOtero JEMbalaviele GDuan XMaruyama TO'Keefe RJAbu-Amer YfalseLDHA-mediated ROS generation in chondrocytes is a potential therapeutic target for osteoarthritis.The contribution of inflammation to the chronic joint disease osteoarthritis (OA) is unclear, and this lack of clarity is detrimental to efforts to identify therapeutic targets. Here we show that chondrocytes under inflammatory conditions undergo a metabolic shift that is regulated by NF-κB activation, leading to reprogramming of cell metabolism towards glycolysis and lactate dehydrogenase A (LDHA). Inflammation and metabolism can reciprocally modulate each other to regulate cartilage degradation. LDHA binds to NADH and promotes reactive oxygen species (ROS) to induce catabolic changes through stabilization of IκB-ζ, a critical pro-inflammatory mediator in chondrocytes. IκB-ζ is regulated bi-modally at the stages of transcription and protein degradation. Overall, this work highlights the f2020-01-01T00:00:00Z2020 Jul2026-07-16T07:12:33.953Z2026-07-09T10:43:28.066ZS-EPMC73476133264717110.1038/s41467-020-17242-0