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The role of extracellular matrix phosphorylation on energy dissipation in bone

  1. Stacyann Bailey  Is a corresponding author
  2. Grazyna E Sroga
  3. Betty Hoac
  4. Orestis L Katsamenis
  5. Zehai Wang
  6. Nikolaos Bouropoulos
  7. Marc D McKee
  8. Esben S Sorenson
  9. Philipp J Thurner
  10. Deepak Vashishth  Is a corresponding author
  1. Rensselaer Polytechnic Institute, United States
  2. McGill University, Canada
  3. University of Southampton, United Kingdom
  4. University of Patras, Greece
  5. Aarhus University, Denmark
  6. Vienna University of Technology, Austria
Research Article
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  • Views 825
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Cite this article as: eLife 2020;9:e58184 doi: 10.7554/eLife.58184

Abstract

Protein phosphorylation, critical for cellular regulatory mechanisms, is implicated in various diseases. However, it remains unknown whether heterogeneity in phosphorylation of key structural proteins alters tissue integrity and organ function. Here, osteopontin phosphorylation level declined in hypo- and hyper- phosphatemia mouse models exhibiting skeletal deformities. Phosphorylation increased cohesion between osteopontin polymers, and adhesion of osteopontin to hydroxyapatite, enhancing energy dissipation. Fracture toughness, a measure of bone's mechanical competence, increased with ex-vivo phosphorylation of wildtype mouse bones and declined with ex-vivo dephosphorylation. In osteopontin deficient mice, global matrix phosphorylation level was not associated with toughness. Our findings suggest that phosphorylated osteopontin promotes fracture toughness in a dose-dependent manner through increased interfacial bond formation. In the absence of osteopontin, phosphorylation increases electrostatic repulsion, protein alignment, and interfilament distance leading to decreased fracture resistance. These mechanisms may be of importance in other connective tissues, and the key to unraveling cell-matrix interactions in diseases.

Data availability

All data generated or analyzed during this study are included in the manuscript and supporting files.

Article and author information

Author details

  1. Stacyann Bailey

    Biomedical Engineering, Rensselaer Polytechnic Institute, Troy, United States
    For correspondence
    stacyann.bailey@mountsinai.org
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9013-2469
  2. Grazyna E Sroga

    Biomedical Engineering, Rensselaer Polytechnic Institute, Troy, United States
    Competing interests
    No competing interests declared.
  3. Betty Hoac

    Faculty of Dentistry, McGill University, Montreal, Canada
    Competing interests
    No competing interests declared.
  4. Orestis L Katsamenis

    Faculty of Engineering and Physical Sciences, University of Southampton, Southampton, United Kingdom
    Competing interests
    No competing interests declared.
  5. Zehai Wang

    Mechanical, Aerospace, and Nuclear Engineering, Rensselaer Polytechnic Institute, Troy, United States
    Competing interests
    No competing interests declared.
  6. Nikolaos Bouropoulos

    Department of Material Science, University of Patras, Patras, Greece
    Competing interests
    No competing interests declared.
  7. Marc D McKee

    Faculty of Dentistry, Department of Anatomy and Cell Biology, Faculty of Medicine, McGill University, Montreal, Canada
    Competing interests
    Marc D McKee, MDM is a member of the FRQS Network for Oral and Bone Health Research, and he holds the Canada Research Chair in Biomineralization as part of the Canada Research Chairs program which contributed to the funding of this work..
  8. Esben S Sorenson

    Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7050-3354
  9. Philipp J Thurner

    Institute of Lightweight Design and Structural Biomechanics, Vienna University of Technology, Vienna, Austria
    Competing interests
    No competing interests declared.
  10. Deepak Vashishth

    Biomedical Engineering, Rensselaer Polytechnic Institute, Troy, United States
    For correspondence
    vashid@rpi.edu
    Competing interests
    No competing interests declared.

Funding

National Institutes of Health (AR 49635)

  • Stacyann Bailey
  • Grazyna E Sroga
  • Zehai Wang
  • Deepak Vashishth

Canadian Institutes of Health Research

  • Betty Hoac
  • Marc D McKee

University of Southampton (Doctoral Prize Fellowship)

  • Orestis L Katsamenis

Canada Research Chairs

  • Marc D McKee

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

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (VAS-001-14) of Rensselaer Polytechnic Institute.

Reviewing Editor

  1. Cheryl Ackert-Bicknell, University of Colorado, United States

Publication history

  1. Received: April 23, 2020
  2. Accepted: December 7, 2020
  3. Accepted Manuscript published: December 9, 2020 (version 1)
  4. Accepted Manuscript updated: December 16, 2020 (version 2)
  5. Version of Record published: December 17, 2020 (version 3)

Copyright

© 2020, Bailey 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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    We gratefully acknowledge support from the Andrew Sabin Family Fellowship, Center for Radiation Oncology Research, Sheikh Ahmed Center for Pancreatic Cancer Research, GE Healthcare, Philips Healthcare, and institutional funds from the University of Texas M.D. Anderson Cancer Center. We have also received Cancer Center Support Grants from the National Cancer Institute (P30CA016672 to the University of Texas M.D. Anderson Cancer Center and P30CA072720 the Rutgers Cancer Institute of New Jersey). This research has also been supported in part by grants from the National Science Foundation Grant DMS-1930583 (ZW, VC), the National Institutes of Health (NIH) 1R01CA253865 (ZW, VC), 1U01CA196403 (ZW, VC), 1U01CA213759 (ZW, VC), 1R01CA226537 (ZW, RP, WA, VC), 1R01CA222007 (ZW, VC), U54CA210181 (ZW, VC), and the University of Texas System STARS Award (VC). BC acknowledges support through the SER Cymru II Programme, funded by the European Commission through the Horizon 2020 Marie Skłodowska-Curie Actions (MSCA) COFUND scheme and the Welsh European Funding Office (WEFO) under the European Regional Development Fund (ERDF). EK has also received support from the Project Purple, NIH (U54CA210181, U01CA200468, and U01CA196403), and the Pancreatic Cancer Action Network (16-65-SING). MF was supported through NIH/NCI center grant U54CA210181, R01CA222959, DoD Breast Cancer Research Breakthrough Level IV Award W81XWH-17-1-0389, and the Ernest Cockrell Jr. Presidential Distinguished Chair at Houston Methodist Research Institute. RP and WA received serial research awards from AngelWorks, the Gillson-Longenbaugh Foundation, and the Marcus Foundation. This work was also supported in part by grants from the National Cancer Institute to SHC (R01CA109322, R01CA127483, R01CA208703, and U54CA210181 CITO pilot grant) and to PYP (R01CA140243, R01CA188610, and U54CA210181 CITO pilot grant). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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