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

Author

Listed:
  • Manoj Arra

    (Washington University School of Medicine)

  • Gaurav Swarnkar

    (Washington University School of Medicine)

  • Ke Ke

    (Washington University School of Medicine)

  • Jesse E. Otero

    (OrthoCarolina Hip and Knee Center)

  • Jun Ying

    (Washington University School of Medicine)

  • Xin Duan
  • Takashi Maruyama

    (Akita University School of Medicine
    National Institutes of Health)

  • Muhammad Farooq Rai

    (Washington University School of Medicine)

  • Regis J. O’Keefe

    (Washington University School of Medicine)

  • Gabriel Mbalaviele

    (Bone and Mineral Division, Department of Medicine, Washington University School of Medicine)

  • Jie Shen

    (Washington University School of Medicine)

  • Yousef Abu-Amer

    (Washington University School of Medicine
    Shriners Hospital for Children)

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.

Suggested Citation

  • Manoj Arra & Gaurav Swarnkar & Ke Ke & Jesse E. Otero & Jun Ying & Xin Duan & Takashi Maruyama & Muhammad Farooq Rai & Regis J. O’Keefe & Gabriel Mbalaviele & Jie Shen & Yousef Abu-Amer, 2020. "LDHA-mediated ROS generation in chondrocytes is a potential therapeutic target for osteoarthritis," Nature Communications, Nature, vol. 11(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-17242-0
    DOI: 10.1038/s41467-020-17242-0
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    Cited by:

    1. Kosei Nagata & Hironori Hojo & Song Ho Chang & Hiroyuki Okada & Fumiko Yano & Ryota Chijimatsu & Yasunori Omata & Daisuke Mori & Yuma Makii & Manabu Kawata & Taizo Kaneko & Yasuhide Iwanaga & Hideki N, 2022. "Runx2 and Runx3 differentially regulate articular chondrocytes during surgically induced osteoarthritis development," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    2. Zhe Gong & Jinjin Zhu & Junxin Chen & Fan Feng & Haitao Zhang & Zheyuan Zhang & Chenxin Song & Kaiyu Liang & Shuhui Yang & Shunwu Fan & Xiangqian Fang & Shuying Shen, 2023. "CircRREB1 mediates lipid metabolism related senescent phenotypes in chondrocytes through FASN post-translational modifications," Nature Communications, Nature, vol. 14(1), pages 1-22, December.

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