Abstract

Senescent cells have detrimental effects across tissues with aging but may have beneficial effects on tissue repair, specifically on skin wound healing. However, the potential role of senescent cells in fracture healing has not been defined. Here, we performed an in silico analysis of public mRNAseq data and found that senescence and senescence-associated secretory phenotype (SASP) markers increased during fracture healing. We next directly established that the expression of senescence biomarkers increased markedly during murine fracture healing. We also identified cells in the fracture callus that displayed hallmarks of senescence, including distension of satellite heterochromatin and telomeric DNA damage; the specific identity of these cells, however, requires further characterization. Then, using a genetic mouse model (Cdkn2aLUC) containing a Cdkn2aInk4a-driven luciferase reporter, we demonstrated transient in vivo senescent cell accumulation during callus formation. Finally, we intermittently treated young adult mice following fracture with drugs that selectively eliminate senescent cells ('senolytics', Dasatinib plus Quercetin), and showed that this regimen both decreased senescence and SASP markers in the fracture callus and significantly accelerated the time course of fracture healing. Our findings thus demonstrate that senescent cells accumulate transiently in the murine fracture callus and, in contrast to the skin, their clearance does not impair but rather improves fracture healing.

Data availability

RNA-seq data was generated from GSE152677.

The following previously published data sets were used

Article and author information

Author details

  1. Dominik Saul

    Division of Endocrinology, Diabetes, Metabolism, Mayo Clinic, Rochester, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0673-3710
  2. David G Monroe

    Division of Endocrinology, Diabetes, Metabolism, Mayo Clinic, Rochester, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Jennifer L Rowsey

    Division of Endocrinology, Diabetes, Metabolism, Mayo Clinic, Rochester, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Robyn Laura Kosinsky

    Division of Endocrinology, Diabetes, Metabolism, Mayo Clinic, Rochester, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Stephanie J Vos

    Division of Endocrinology, Diabetes, Metabolism, Mayo Clinic, Rochester, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Madison L Doolittle

    Division of Endocrinology, Diabetes, Metabolism, Mayo Clinic, Rochester, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Joshua N Farr

    Endocrinology, Mayo Clinic, Rochester, United States
    For correspondence
    Farr.Joshua@mayo.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3179-6414
  8. Sundeep Khosla MD

    Endocrinology, Mayo Clinic, Rochester, United States
    For correspondence
    khosla.sundeep@mayo.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2936-4372

Funding

National Institute on Aging (P01 AG062413)

  • Joshua N Farr

National Institute on Aging (R21 AG065868)

  • Joshua N Farr

National Institute on Aging (R01 AG063707)

  • David G Monroe

National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK128552)

  • Joshua N Farr

German Research Foundation (413501650)

  • Dominik Saul

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

Reviewing Editor

  1. Subburaman Mohan, Loma Linda University, United States

Ethics

Animal experimentation: Animal studies were performed under protocols approved by the Institutional Animal Care and Use Committee (IACUC), and experiments were performed in accordance with Mayo Clinic IACUC guidelines.

Version history

  1. Received: May 2, 2021
  2. Preprint posted: May 19, 2021 (view preprint)
  3. Accepted: September 29, 2021
  4. Accepted Manuscript published: October 7, 2021 (version 1)
  5. Version of Record published: October 19, 2021 (version 2)

Copyright

© 2021, Saul 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. Dominik Saul
  2. David G Monroe
  3. Jennifer L Rowsey
  4. Robyn Laura Kosinsky
  5. Stephanie J Vos
  6. Madison L Doolittle
  7. Joshua N Farr
  8. Sundeep Khosla MD
(2021)
Modulation of fracture healing by the transient accumulation of senescent cells
eLife 10:e69958.
https://doi.org/10.7554/eLife.69958

Share this article

https://doi.org/10.7554/eLife.69958

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