Journal
NATURE COMMUNICATIONS
Volume 11, Issue 1, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-020-17242-0
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Funding
- NIH/NIAMS [R01-AR064755, R01-AR068972, R01-AR049192, R01-AR054326, R01-AR072623]
- Biomedical grant from Shriners Hospital for Children [85160]
- NIH Core Center for Musculoskeletal Biology and Medicine [P30 AR057235]
- [R01-AR075860]
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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-kappa B 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 I kappa B-zeta, a critical pro-inflammatory mediator in chondrocytes. I kappa B-zeta is regulated bi-modally at the stages of transcription and protein degradation. Overall, this work highlights the function of NF-kappa B 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.
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