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

  • Nat Commun. 2020 Jul 9;11(1):3427. doi: 10.1038/s41467-020-17242-0.
Manoj Arra  1 ,  Gaurav Swarnkar  1 ,  Ke Ke  1 ,  Jesse E Otero  2 ,  Jun Ying  1 ,  Xin Duan ,  Takashi Maruyama  3  4 ,  Muhammad Farooq Rai  1 ,  Regis J O'Keefe  1 ,  Gabriel Mbalaviele  5 ,  Jie Shen  1 ,  Yousef Abu-Amer  6  7
Affiliations
  • 1. Department of Orthopaedic Surgery and Cell Biology & Physiology, Washington University School of Medicine, St. Louis, MO, 63110, USA.
  • 2. OrthoCarolina Hip and Knee Center, Charlotte, NC, 28207, USA.
  • 3. Department of Immunology, Akita University School of Medicine, Akita, Japan.
  • 4. Mucosal Immunology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, 20892, USA.
  • 5. Bone and Mineral Division, Department of Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA.
  • 6. Department of Orthopaedic Surgery and Cell Biology & Physiology, Washington University School of Medicine, St. Louis, MO, 63110, USA. [email protected].
  • 7. Shriners Hospital for Children, St. Louis, MO, 63110, USA. [email protected].
PMID: 32647171 DOI: 10.1038/s41467-020-17242-0
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.

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