LDHA-mediated ROS generation in chondrocytes is a potential therapeutic target for osteoarthritis

• Published in: Nature communications 2020-07, Vol.11 (1), p.3427-16, Article 3427
• Main Authors: Arra, Manoj, Swarnkar, Gaurav, Ke, Ke, Otero, Jesse E., Ying, Jun, Duan, Xin, Maruyama, Takashi, Rai, Muhammad Farooq, O’Keefe, Regis J., Mbalaviele, Gabriel, Shen, Jie, Abu-Amer, Yousef
• Format: Article
• Language: English
• Subjects: 13/1; 13/106; 13/21; 13/51; 13/95; 14/5; 38/91; 59/5; 631/250/256; 631/443/319; 64/60; 692/4023/1670/407; 692/4023/1671/1354; 82/1; Adaptor Proteins, Signal Transducing - metabolism; Aerobiosis; Animals; Arthritis; Biodegradation; Biomedical materials; Cartilage; Cartilage diseases; Cartilage, Articular - pathology; Catabolism; Cells, Cultured; Chondrocytes; Chondrocytes - drug effects; Chondrocytes - metabolism; Chondrocytes - pathology; Cytoprotection - drug effects; Degradation; Gene Deletion; Gene Expression Regulation - drug effects; Glycolysis; Glycolysis - drug effects; Humanities and Social Sciences; Humans; Inflammation; Inflammation - metabolism; Inflammation - pathology; Interleukin-1beta - pharmacology; Joint diseases; Knee Joint - pathology; L-Lactate dehydrogenase; Lactate dehydrogenase; Lactate Dehydrogenase 5 - metabolism; Lactic acid; Menisci, Tibial - surgery; Metabolic Networks and Pathways - drug effects; Metabolism; Mice, Inbred C57BL; Molecular Targeted Therapy; multidisciplinary; NAD - metabolism; NADH; NF-kappa B - metabolism; NF-κB protein; Nicotinamide adenine dinucleotide; Osteoarthritis; Osteoarthritis - drug therapy; Osteoarthritis - genetics; Osteoarthritis - pathology; Reactive oxygen species; Reactive Oxygen Species - metabolism; Science; Science (multidisciplinary); Target recognition; Therapeutic applications; Transcription
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-17242-0

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. Chondrocytes have altered cellular metabolism in the context of osteoarthritis, but whether and how these changes are associated with inflammation is a controversial area. Here the authors show that inflammatory NF-κB signalling drives a glycolytic shift in chondrocytes and the production of ROS, which drives cartilage catabolism.