Parathyroid hormone attenuates osteoarthritis pain by remodeling subchondral bone in mice

  1. Qi Sun
  2. Gehua Zhen
  3. Tuo Peter Li
  4. Qiaoyue Guo
  5. Yusheng Li
  6. Weiping Su
  7. Peng Xue
  8. Xiao Wang
  9. Mei Wan
  10. Yun Guan
  11. Xinzhong Dong
  12. Shaohua Li
  13. Ming Cai
  14. Xu Cao  Is a corresponding author
  1. Johns Hopkins University School of Medicine, United States
  2. Shanghai Tenth People's Hospital, Tongji University School of Medicine, China

Abstract

Osteoarthritis, a highly prevalent degenerative joint disorder, is characterized by joint pain and disability. Available treatments fail to modify osteoarthritis progression and decrease joint pain effectively. Here, we show that intermittent parathyroid hormone (iPTH) attenuates osteoarthritis pain by inhibiting subchondral sensory innervation, subchondral bone deterioration, and articular cartilage degeneration in a destabilized medial meniscus (DMM) mouse model. We found that subchondral sensory innervation for osteoarthritis pain was significantly decreased in PTH-treated DMM mice compared with vehicle-treated DMM mice. In parallel, deterioration of subchondral bone microarchitecture in DMM mice was attenuated by iPTH treatment. Increased level of prostaglandin E2 in subchondral bone of DMM mice was reduced by iPTH treatment. Furthermore, uncoupled subchondral bone remodeling caused by increased transforming growth factor β signaling was regulated by PTH-induced endocytosis of the PTH type 1 receptor–transforming growth factor β type 2 receptor complex. Notably, iPTH improved subchondral bone microarchitecture, and decreased level of prostaglandin E2 and sensory innervation of subchondral bone in DMM mice by acting specifically through PTH type 1 receptor in Nestin+ mesenchymal stromal cells. Thus, iPTH could be a potential disease-modifying therapy for osteoarthritis.

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. Qi Sun

    Orthopedic Surgery, Johns Hopkins University School of Medicine, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Gehua Zhen

    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:" 0000-0001-7652-6226
  3. Tuo Peter Li

    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:" 0000-0002-4302-9538
  4. Qiaoyue Guo

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

    Orthopedic Surgery, Johns Hopkins University School of Medicine, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Weiping Su

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

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

    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:" 0000-0001-6395-706X
  9. 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
  10. Yun Guan

    Neuroscience, Johns Hopkins University School of Medicine, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. 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
  12. Shaohua Li

    Orthopedic Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.
  13. Ming Cai

    Orthopedic Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.
  14. 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 (P01AG066603)

  • Xu Cao

National Institutes of Health (1R01 AG068997)

  • Xu Cao

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

Reviewing Editor

  1. Di Chen

Ethics

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

Version history

  1. Received: January 14, 2021
  2. Accepted: February 26, 2021
  3. Accepted Manuscript published: March 1, 2021 (version 1)
  4. Version of Record published: March 31, 2021 (version 2)

Copyright

© 2021, Sun 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. Qi Sun
  2. Gehua Zhen
  3. Tuo Peter Li
  4. Qiaoyue Guo
  5. Yusheng Li
  6. Weiping Su
  7. Peng Xue
  8. Xiao Wang
  9. Mei Wan
  10. Yun Guan
  11. Xinzhong Dong
  12. Shaohua Li
  13. Ming Cai
  14. Xu Cao
(2021)
Parathyroid hormone attenuates osteoarthritis pain by remodeling subchondral bone in mice
eLife 10:e66532.
https://doi.org/10.7554/eLife.66532

Share this article

https://doi.org/10.7554/eLife.66532

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