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Activation of Nrf2 signaling by 4-octyl itaconate attenuates the cartilaginous endplate degeneration by inhibiting E3 ubiquitin ligase ZNF598

  • Author Footnotes
    a Bao Huang, Haihao Wu and Lin Zheng contributed equally to this work and should be regarded as the cofirst authors.
    B. Huang
    Footnotes
    a Bao Huang, Haihao Wu and Lin Zheng contributed equally to this work and should be regarded as the cofirst authors.
    Affiliations
    Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, No. 3, Qingchun Road East, Hangzhou, 310016, PR China

    Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, No. 3, Qingchun Road East, Hangzhou, 310016, PR China
    Search for articles by this author
  • Author Footnotes
    a Bao Huang, Haihao Wu and Lin Zheng contributed equally to this work and should be regarded as the cofirst authors.
    H. Wu
    Footnotes
    a Bao Huang, Haihao Wu and Lin Zheng contributed equally to this work and should be regarded as the cofirst authors.
    Affiliations
    Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, No. 3, Qingchun Road East, Hangzhou, 310016, PR China

    Department of Orthopedics Surgery, Hwa Mei Hospital, University of Chinese Academy of Sciences, No. 41, Northwest Street, Ningbo, 315010, Zhejiang, PR China
    Search for articles by this author
  • Author Footnotes
    a Bao Huang, Haihao Wu and Lin Zheng contributed equally to this work and should be regarded as the cofirst authors.
    L. Zheng
    Footnotes
    a Bao Huang, Haihao Wu and Lin Zheng contributed equally to this work and should be regarded as the cofirst authors.
    Affiliations
    Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, No. 3, Qingchun Road East, Hangzhou, 310016, PR China

    Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, No. 3, Qingchun Road East, Hangzhou, 310016, PR China
    Search for articles by this author
  • X. Wei
    Affiliations
    Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, No. 3, Qingchun Road East, Hangzhou, 310016, PR China

    Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, No. 3, Qingchun Road East, Hangzhou, 310016, PR China
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  • Z. Zheng
    Affiliations
    Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, No. 3, Qingchun Road East, Hangzhou, 310016, PR China

    Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, No. 3, Qingchun Road East, Hangzhou, 310016, PR China
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  • H. Wu
    Affiliations
    Department of Orthopaedics and Traumatology, The University of Hong Kong, Pokfulam, Hong Kong, SAR, PR China
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  • J. Chen
    Affiliations
    Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, No. 3, Qingchun Road East, Hangzhou, 310016, PR China

    Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, No. 3, Qingchun Road East, Hangzhou, 310016, PR China
    Search for articles by this author
  • Z. Shan
    Affiliations
    Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, No. 3, Qingchun Road East, Hangzhou, 310016, PR China

    Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, No. 3, Qingchun Road East, Hangzhou, 310016, PR China
    Search for articles by this author
  • J. Liu
    Correspondence
    Address correspondence and reprint requests to: J. Liu, No. 3, Qingchun Road East, Hangzhou, 310016, PR China. Tel: 86-13656674562.
    Affiliations
    Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, No. 3, Qingchun Road East, Hangzhou, 310016, PR China

    Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, No. 3, Qingchun Road East, Hangzhou, 310016, PR China
    Search for articles by this author
  • F. Zhao
    Correspondence
    Address correspondence and reprint requests to: F. Zhao, No. 3, Qingchun Road East, Hangzhou, 310016, PR China. Tel: 86-13858120759; Fax: 86-571-86044817.
    Affiliations
    Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, No. 3, Qingchun Road East, Hangzhou, 310016, PR China

    Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, No. 3, Qingchun Road East, Hangzhou, 310016, PR China
    Search for articles by this author
  • Author Footnotes
    a Bao Huang, Haihao Wu and Lin Zheng contributed equally to this work and should be regarded as the cofirst authors.
Published:October 17, 2022DOI:https://doi.org/10.1016/j.joca.2022.10.008

      Summary

      Objective

      Cartilaginous endplate (CEP) degeneration is the main early manifestations of intervertebral disc degeneration (IVDD), and is closely related to the oxidative stress. Nrf2 (nuclear factor E2-related factor 2, NFE2L2) is a vital transcriptional factor of cellular antioxidant and anti-inflammatory responses. We aimed to illustrate whether the Nrf2 which was increased in expression by 4-octyl itaconate (4OI) could attenuate intervertebral disc degeneration through suppressing macrophage associated inflammation and catabolism of cartilaginous endplate.

      Methods

      Firstly, we detected the expression of Nrf2 in human degenerative CEPs. Then, we performed in vitro, ex vivo and in vivo (a rat-tail puncture model) experiments to explore the role of 4OI in IVDD. Also, by cell co-culture experiments, we demonstrated 4OI restrained the macrophage-associated inflammatory responses. Finally, through western blotting and immunoprecipitation (IP) assay, we clarified the ZNF598-mediated ubiquitination of Nrf2.

      Results

      We found decreased expression of Nrf2 in human degenerative CEPs. Using a rat IVDD model(n = 6), 4OI significantly ameliorated the progression of IVDD by MR images and histological analysis. Immunofluorescence results reveal that catabolism of CEPs and macrophage-associated inflammation are suppressed by 4OI treatment. Mechanistically, the 4OI increases Nrf2 expression and inhibits the secretion of inflammatory factors (IL-1β) by Lipopolysaccharide (LPS)-induced macrophages, thus preventing the inflammatory-related CEP degeneration. Meanwhile, 4OI suppresses the reactive oxygen species (ROS) production and catabolism of LPS-induced rat CEP cells. In addition, 4OI inhibits the ZNF598-dependent ubiquitination of Nrf2 in LPS-induced rat CEP cells.

      Conclusions

      4OI may alleviate IVDD by suppressing CEP degeneration and macrophage-associated inflammation. 4OI may be an alternative therapy for degenerative CEPs/IVDs.

      Keywords

      Abbreviations:

      LBP (low back pain), CEP (cartilaginous endplate), NP (nucleus pulposus), IVDD (Intervertebral disc degeneration), MMP (matrix metalloprotease), ECM (extracellular matrix), NFE2L2 (nuclear factor E2-related factor 2), 4OI (4-octyl itaconate), MitoSOX (mitochondrial superoxide), IL-1β (interleukin 1β), TNF-α (tumor necrosis factor α)
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