Mechanically-stimulated ATP release from murine bone cells is regulated by a balance of injury and repair

  1. Nicholas Mikolajewicz
  2. Elizabeth A Zimmermann
  3. Bettina M Willie
  4. Svetlana V Komarova  Is a corresponding author
  1. McGill University, Canada
  2. Shriners Hospital for Children-Canada, Canada

Abstract

Bone cells sense and actively adapt to physical perturbations to prevent critical damage. ATP release is among the earliest cellular responses to mechanical stimulation. Mechanical stimulation of a single murine osteoblast led to the release of 70 {plus minus} 24 amole ATP, which stimulated calcium responses in neighboring cells. Osteoblasts contained ATP-rich vesicles that were released upon mechanical stimulation. Surprisingly, interventions that promoted vesicular release reduced ATP release, while inhibitors of vesicular release potentiated ATP release. Searching for an alternative ATP release route, we found that mechanical stresses induced reversible cell membrane injury in vitro and in vivo. Ca2+/PLC/PKC-dependent vesicular exocytosis facilitated membrane repair, thereby minimizing cell injury and reducing ATP release. Priming cellular repair machinery prior to mechanical stimulation reduced subsequent membrane injury and ATP release, linking cellular mechanosensitivity to prior mechanical exposure. Thus, our findings position ATP release as an integrated readout of membrane injury and repair.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for Figures 1-6. Representative video recordings and confocal z-stacks are included as rich media files.

Article and author information

Author details

  1. Nicholas Mikolajewicz

    Faculty of Dentistry, McGill University, Montreal, Canada
    Competing interests
    The authors declare that no competing interests exist.
  2. Elizabeth A Zimmermann

    Shriners Hospital for Children-Canada, Montreal, Canada
    Competing interests
    The authors declare that no competing interests exist.
  3. Bettina M Willie

    Shriners Hospital for Children-Canada, Montreal, Canada
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2907-3580
  4. Svetlana V Komarova

    Faculty of Dentistry, McGill University, Montreal, Canada
    For correspondence
    svetlana.komarova@mcgill.ca
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3570-3147

Funding

Canadian Institutes of Health Research (MOP-77643)

  • Svetlana V Komarova

Natural Sciences and Engineering Research Council of Canada (RGPIN-288253)

  • Svetlana V Komarova

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 procedures were approved by McGill's University's Animal Care Committee and complied with the ethical guidelines of the Canadian Council on Animal Care. (protocols # 2012-7127 and 2016-7821)

Reviewing Editor

  1. Miguel A Valverde, Pompeu Fabra University, Spain

Publication history

  1. Received: April 23, 2018
  2. Accepted: September 28, 2018
  3. Accepted Manuscript published: October 16, 2018 (version 1)
  4. Version of Record published: October 29, 2018 (version 2)

Copyright

© 2018, Mikolajewicz 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. Nicholas Mikolajewicz
  2. Elizabeth A Zimmermann
  3. Bettina M Willie
  4. Svetlana V Komarova
(2018)
Mechanically-stimulated ATP release from murine bone cells is regulated by a balance of injury and repair
eLife 7:e37812.
https://doi.org/10.7554/eLife.37812

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