p16 deficiency attenuates intervertebral disc degeneration by adjusting oxidative stress and nucleus pulposus cell cycle

  1. Hui Che
  2. Jie Li
  3. You Li
  4. Cheng Ma
  5. Huan Liu
  6. Jingyi Qin
  7. Jianghui Dong
  8. Zhen Zhang
  9. Cory J Xian
  10. Dengshun Miao
  11. Liping Wang  Is a corresponding author
  12. Yongxin Ren  Is a corresponding author
  1. The First Affiliated Hospital of Nanjing Medical University, China
  2. Xuzhou Central Hospital, China
  3. Chinese Academy of Sciences, China
  4. University of South Australia, Australia
  5. Nanjing Medical University, China

Abstract

Cell cycle regulator p16 is known a biomarker and an effector of aging. However, its function in intervertebral disc degeneration (IVDD) is unclear. In this study, p16 expression levels were found positively correlated with severity of human IVDD. In a mouse tail suspension (TS)-induced IVDD model, lumbar intervertebral disc height index and matrix protein expression levels were reduced significantly were largely rescued by p16 deletion. In TS mouse discs, reactive oxygen species levels, proportions of senescent cells, and senescence-associated secretory phenotype (SASP) were increased; cell cycling was delayed; and expression was downregulated for Sirt1, superoxide dismutase 1/2, cyclin-dependent kinases 4/6, phosphorylated retinoblastoma protein, and transcription factor E2F1/2. However, these effects were rescued by p16 deletion. Our results demonstrate that p16 plays an important role in IVDD pathogenesis and that its deletion attenuates IVDD by promoting cell cycling and inhibiting SASP, cell senescence, and oxidative stress.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files.

Article and author information

Author details

  1. Hui Che

    Department of Orthopaedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3345-2033
  2. Jie Li

    Department of Orthopaedics, Xuzhou Central Hospital, Xuzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  3. You Li

    Department of Orthopaedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
    Competing interests
    The authors declare that no competing interests exist.
  4. Cheng Ma

    Department of Orthopaedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
    Competing interests
    The authors declare that no competing interests exist.
  5. Huan Liu

    Department of Orthopaedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
    Competing interests
    The authors declare that no competing interests exist.
  6. Jingyi Qin

    Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  7. Jianghui Dong

    School of Pharmacy and Medical Sciences, and UniSA Cancer Research Institute, University of South Australia, Adelaide, Australia
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3961-1688
  8. Zhen Zhang

    School of Pharmacy and Medical Sciences, and UniSA Cancer Research Institute, University of South Australia, Adelaide, Australia
    Competing interests
    The authors declare that no competing interests exist.
  9. Cory J Xian

    School of Pharmacy and Medical Sciences, and UniSA Cancer Research Institute, University of South Australia, Adelaide, Australia
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8467-2845
  10. Dengshun Miao

    Department of Anatomy, Histology and Embryology, Nanjing Medical University, Nanjing, China
    Competing interests
    The authors declare that no competing interests exist.
  11. Liping Wang

    School of Pharmacy and Medical Sciences, and UniSA Cancer Research Institute, University of South Australia, Adelaide, Australia
    For correspondence
    liping.wang@mymail.unisa.edu.au
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9355-1167
  12. Yongxin Ren

    Department of Orthopaedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
    For correspondence
    renyongxinjsph@163.com
    Competing interests
    The authors declare that no competing interests exist.

Funding

National Health and Medical Research Council (1158402)

  • Liping Wang

National Natural Science Foundation of China (81572149)

  • Dengshun Miao
  • Yongxin Ren

China Scholarship Council (CSC201908080215)

  • Hui Che

National Natural Science Foundation of China (81671928)

  • Cory J Xian
  • Liping Wang

National Health and Medical Research Council (1127396)

  • Cory J Xian

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: Animal use was approved by the Institutional Animal Care and Use Committee of Nanjing Medical University (approval number: IACUC-1709021).

Human subjects: This work was implemented by the approval of the Ethics Committee of The First Affiliated Hospital of Nanjing Medical University (approval number: 2018-SR-233). Before the operation, the informed consents of the patients have been obtained, including the patient's voluntary donation of the diseased nucleus pulposus tissue extracted from the operation, and their consents that all specimens will be used for scientific research and the results obtained will be published in scientific journals.

Reviewing Editor

  1. Mone Zaidi, Icahn School of Medicine at Mount Sinai, United States

Publication history

  1. Received: October 8, 2019
  2. Accepted: February 12, 2020
  3. Accepted Manuscript published: March 3, 2020 (version 1)
  4. Version of Record published: March 11, 2020 (version 2)

Copyright

© 2020, Che et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Hui Che
  2. Jie Li
  3. You Li
  4. Cheng Ma
  5. Huan Liu
  6. Jingyi Qin
  7. Jianghui Dong
  8. Zhen Zhang
  9. Cory J Xian
  10. Dengshun Miao
  11. Liping Wang
  12. Yongxin Ren
(2020)
p16 deficiency attenuates intervertebral disc degeneration by adjusting oxidative stress and nucleus pulposus cell cycle
eLife 9:e52570.
https://doi.org/10.7554/eLife.52570

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