Abstract
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 function of NF-κB activity in the OA joint as well as a ROS promoting function for LDHA and identifies LDHA as a potential therapeutic target for OA treatment.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / metabolism
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Aerobiosis
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Animals
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Cartilage, Articular / pathology
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Cells, Cultured
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Chondrocytes / drug effects
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Chondrocytes / metabolism*
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Chondrocytes / pathology
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Cytoprotection / drug effects
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Gene Deletion
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Gene Expression Regulation / drug effects
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Glycolysis / drug effects
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Humans
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Inflammation / metabolism
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Inflammation / pathology
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Interleukin-1beta / pharmacology
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Knee Joint / pathology
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Lactate Dehydrogenase 5 / metabolism*
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Menisci, Tibial / surgery
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Metabolic Networks and Pathways / drug effects
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Mice, Inbred C57BL
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Molecular Targeted Therapy*
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NAD / metabolism
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NF-kappa B / metabolism
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Osteoarthritis / drug therapy*
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Osteoarthritis / genetics
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Osteoarthritis / pathology
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Reactive Oxygen Species / metabolism*
Substances
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Adaptor Proteins, Signal Transducing
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Interleukin-1beta
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NF-kappa B
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Nfkbiz protein, mouse
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Reactive Oxygen Species
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NAD
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Lactate Dehydrogenase 5