Fracture healing is delayed in the absence of gasdermin - interleukin-1 signaling

  1. Kai Sun
  2. Chun Wang
  3. Jianqiu Xiao
  4. Michael D Brodt
  5. Luorongxin Yuan
  6. Tong Yang
  7. Yael Alippe
  8. Huimin Hu
  9. Dingjun Hao
  10. Yousef Abu-Amer
  11. Matthew J Silva
  12. Jie Shen
  13. Gabriel Mbalaviele  Is a corresponding author
  1. Washington University School of Medicine, United States
  2. First Affiliated Hospital of Xi'an Jiaotong University, China

Abstract

Amino-terminal fragments from proteolytically cleaved gasdermins (GSDMs) form plasma membrane pores that enable the secretion of interleukin-1β (IL-1β) and IL-18. Excessive GSDM-mediated pore formation can compromise the integrity of the plasma membrane thereby causing the lytic inflammatory cell death, pyroptosis. We found that GSDMD and GSDME were the only GSDMs that were readily expressed in bone microenvironment. Therefore, we tested the hypothesis that GSDMD and GSDME are implicated in fracture healing owing to their role in the obligatory inflammatory response following injury. We found that bone callus volume and biomechanical properties of injured bones were significantly reduced in mice lacking either GSDM compared with wild-type (WT) mice, indicating that fracture healing was compromised in mutant mice. However, compound loss of GSDMD and GSDME did not exacerbate the outcomes, suggesting shared actions of both GSDMs in fracture healing. Mechanistically, bone injury induced IL-1β and IL-18 secretion in vivo, a response that was mimicked in vitro by bone debris and ATP, which function as inflammatory danger signals. Importantly, the secretion of these cytokines was attenuated in conditions of GSDMD deficiency. Finally, deletion of IL-1 receptor reproduced the phenotype of Gsdmd or Gsdme deficient mice, implying that inflammatory responses induced by the GSDM-IL-1 axis promote bone healing after fracture.

Data availability

All data generated or analy5ed during this study are included in the manuscript and supporting file; Source Data files have been provided for all figures.

Article and author information

Author details

  1. Kai Sun

    Division of Bone and Mineral Diseases, Washington University School of Medicine, St. Louis, United States
    Competing interests
    No competing interests declared.
  2. Chun Wang

    Division of Bone and Mineral Diseases, Washington University School of Medicine, St. Louis, United States
    Competing interests
    No competing interests declared.
  3. Jianqiu Xiao

    Division of Bone and Mineral Diseases, Washington University School of Medicine, St. Louis, United States
    Competing interests
    No competing interests declared.
  4. Michael D Brodt

    Department of Orthopaedic Surgery, Washington University School of Medicine, St. Louis, United States
    Competing interests
    No competing interests declared.
  5. Luorongxin Yuan

    Division of Bone and Mineral Diseases, Washington University School of Medicine, St. Louis, United States
    Competing interests
    No competing interests declared.
  6. Tong Yang

    Division of Bone and Mineral Diseases, Washington University School of Medicine, St. Louis, United States
    Competing interests
    No competing interests declared.
  7. Yael Alippe

    Division of Bone and Mineral Diseases, Washington University School of Medicine, St. Louis, United States
    Competing interests
    No competing interests declared.
  8. Huimin Hu

    Department of Spine Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
    Competing interests
    No competing interests declared.
  9. Dingjun Hao

    Department of Spine Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
    Competing interests
    No competing interests declared.
  10. Yousef Abu-Amer

    Department of Orthopaedic Surgery, Washington University School of Medicine, Saint Louis, United States
    Competing interests
    Yousef Abu-Amer, Reviewing editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5890-5086
  11. Matthew J Silva

    Department of Orthopaedic Surgery, Washington University School of Medicine, Saint Louis, United States
    Competing interests
    No competing interests declared.
  12. Jie Shen

    Department of Orthopaedic Surgery, Washington University School of Medicine, Saint Louis, United States
    Competing interests
    No competing interests declared.
  13. Gabriel Mbalaviele

    Division of Bone and Mineral Diseases, Washington University School of Medicine, St. Louis, United States
    For correspondence
    gmbalaviele@WUSTL.EDU
    Competing interests
    Gabriel Mbalaviele, Consultant for Aclaris Therapeutics, Inc..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4660-0952

Funding

National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR076758)

  • Gabriel Mbalaviele

National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR074992)

  • Matthew J Silva

National Institute of Allergy and Infectious Diseases (AI161022)

  • Gabriel Mbalaviele

National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR075860)

  • Jie Shen

National Institute of Allergy and Infectious Diseases (AR077616)

  • Jie Shen

National Institute of Allergy and Infectious Diseases (AR077226)

  • Jie Shen

National Institute of Allergy and Infectious Diseases (AR049192)

  • Yousef Abu-Amer

National Institute of Allergy and Infectious Diseases (AR074992)

  • Yousef Abu-Amer

National Institute of Allergy and Infectious Diseases (AR072623)

  • Yousef Abu-Amer

Shriners Hospitals for Children (85160)

  • Yousef Abu-Amer

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

Reviewing Editor

  1. Fayez Safadi, Northeast Ohio Medical University, United States

Ethics

Animal experimentation: All mice were on the C57BL6J background, and genotyping was performed by PCR. All procedures were approved by the Institutional Animal Care and Use Committee (IACUC) of Washington University School of Medicine in St. Louis. All experiments were performed in accordance with the relevant guidelines and regulations described in the IACUC- approved protocol 19-0971.

Version history

  1. Received: November 22, 2021
  2. Preprint posted: November 29, 2021 (view preprint)
  3. Accepted: February 27, 2022
  4. Accepted Manuscript published: March 4, 2022 (version 1)
  5. Version of Record published: March 15, 2022 (version 2)

Copyright

© 2022, 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. Kai Sun
  2. Chun Wang
  3. Jianqiu Xiao
  4. Michael D Brodt
  5. Luorongxin Yuan
  6. Tong Yang
  7. Yael Alippe
  8. Huimin Hu
  9. Dingjun Hao
  10. Yousef Abu-Amer
  11. Matthew J Silva
  12. Jie Shen
  13. Gabriel Mbalaviele
(2022)
Fracture healing is delayed in the absence of gasdermin - interleukin-1 signaling
eLife 11:e75753.
https://doi.org/10.7554/eLife.75753

Share this article

https://doi.org/10.7554/eLife.75753

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