1. Medicine
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Aberrant subchondral osteoblastic metabolism modifies NaV1.8 for osteoarthritis

  1. Jianxi Zhu
  2. Gehua Zhen
  3. Senbo An
  4. Xiao Wang
  5. Mei Wan
  6. Yusheng Li
  7. Zhiyong Chen
  8. Yun Guan
  9. Xinzhong Dong
  10. Yihe hu  Is a corresponding author
  11. Xu Cao  Is a corresponding author
  1. Xiangya Hospital, Central South University, China
  2. Johns Hopkins University School of Medicine, United States
Research Article
  • Cited 4
  • Views 1,523
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Cite this article as: eLife 2020;9:e57656 doi: 10.7554/eLife.57656

Abstract

Pain is the most prominent symptom of osteoarthritis (OA) progression. However, the relationship between pain and OA progression remains largely unknown. Here we report osteoblast secret prostaglandin E2 (PGE2) during aberrant subchondral bone remodeling induces pain and OA progression in mice. Specific deletion of the major PGE2 producing enzyme cyclooxygenase 2 (COX2) in osteoblasts or PGE2 receptor EP4 in peripheral nerve markedly ameliorates OA symptoms. Mechanistically, PGE2 sensitizes dorsal root ganglia (DRG) neurons by modifying the voltage-gated sodium channel NaV1.8, evidenced by that genetically or pharmacologically inhibiting NaV1.8 in DRG neurons can substantially attenuate OA. Moreover, drugs targeting aberrant subchondral bone remodeling also attenuates OA through rebalancing PGE2 production and NaV1.8 modification. Thus, aberrant subchondral remodeling induced NaV1.8 neuronal modification is an important player in OA and is a potential therapeutic target in multiple skeletal degenerative diseases.

Article and author information

Author details

  1. Jianxi Zhu

    Orthopaedics, Xiangya Hospital, Central South University, Changsha, China
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4637-0704
  2. Gehua Zhen

    Orthopedic Surgery, Johns Hopkins University School of Medicine, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Senbo An

    Orthopedic Surgery, Johns Hopkins University School of Medicine, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Xiao Wang

    Orthopedic Surgery, Johns Hopkins University School of Medicine, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Mei Wan

    Orthopedic Surgery, Johns Hopkins University School of Medicine, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9404-540X
  6. Yusheng Li

    Orthopedic Surgery, Johns Hopkins University School of Medicine, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Zhiyong Chen

    Orthopedic Surgery, Johns Hopkins University School of Medicine, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Yun Guan

    Neuroscience, Johns Hopkins University School of Medicine, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Xinzhong Dong

    Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9750-7718
  10. Yihe hu

    Orthopaedics, Xiangya Hospital, Central South University, Changsha, China
    For correspondence
    huyh1964@163.com
    Competing interests
    The authors declare that no competing interests exist.
  11. Xu Cao

    Orthopedic Surgery, Johns Hopkins University School of Medicine, Baltimore, United States
    For correspondence
    xcao11@jhmi.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8614-6059

Funding

National Institutes of Health (AR071432)

  • Xu Cao

National Institutes of Health (AR063943)

  • Xu Cao

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

Ethics

Animal experimentation: All animal experiments were approved by the Institutional Animal Care andUse of Johns Hopkins University, School of Medicine. (Protocol number: Mo18M308).

Human subjects: human study was approved by the Johns Hopkins Medicine Institutional ReviewBoards. Written informed consent and consent to publish forms were obtained from all volunteers prior to providing samples. (Protocol number: Mo18M308).

Reviewing Editor

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

Publication history

  1. Received: April 8, 2020
  2. Accepted: May 19, 2020
  3. Accepted Manuscript published: May 22, 2020 (version 1)
  4. Version of Record published: June 22, 2020 (version 2)

Copyright

© 2020, Zhu 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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