1. Medicine

The role of extracellular matrix phosphorylation on energy dissipation in bone

  1. Stacyann Bailey
  2. Grazyna E Sroga
  3. Betty Hoac
  4. Orestis L Katsamenis
  5. Zehai Wang
  6. Nikolaos Bouropoulos
  7. Marc D McKee
  8. Esben S Sorensen
  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
https://doi.org/10.7554/eLife.58184
Share this article
Cite this article
  1. Stacyann Bailey
  2. Grazyna E Sroga
  3. Betty Hoac
  4. Orestis L Katsamenis
  5. Zehai Wang
  6. Nikolaos Bouropoulos
  7. Marc D McKee
  8. Esben S Sorensen
  9. Philipp J Thurner
  10. Deepak Vashishth
(2020)
The role of extracellular matrix phosphorylation on energy dissipation in bone
eLife 9:e58184.
https://doi.org/10.7554/eLife.58184
  2. Download BibTeX
  3. Download .RIS

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
    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 Sorensen

    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.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5712-0167

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

Version 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.

Metrics

  • 1,235
    Page views
  • 139
    Downloads
  • 7
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Stacyann Bailey
  2. Grazyna E Sroga
  3. Betty Hoac
  4. Orestis L Katsamenis
  5. Zehai Wang
  6. Nikolaos Bouropoulos
  7. Marc D McKee
  8. Esben S Sorensen
  9. Philipp J Thurner
  10. Deepak Vashishth
(2020)
The role of extracellular matrix phosphorylation on energy dissipation in bone
eLife 9:e58184.
https://doi.org/10.7554/eLife.58184

Categories and tags

Research organism

Further reading

    1. Medicine

    SIRT2 inhibition protects against cardiac hypertrophy and ischemic injury

    Xiaoyan Yang, Hsiang-Chun Chang ... Hossein Ardehali
    Research Article

    Sirtuins (SIRT) exhibit deacetylation or ADP-ribosyltransferase activity and regulate a wide range of cellular processes in the nucleus, mitochondria and cytoplasm. The role of the only sirtuin that resides in the cytoplasm, SIRT2, in the development of ischemic injury and cardiac hypertrophy is not known. In this paper, we show that the hearts of mice with deletion of Sirt2 (Sirt2-/-) display improved cardiac function after ischemia-reperfusion (I/R) and pressure overload (PO), suggesting that SIRT2 exerts maladaptive effects in the heart in response to stress. Similar results were obtained in mice with cardiomyocyte-specific Sirt2 deletion. Mechanistic studies suggest that SIRT2 modulates cellular levels and activity of nuclear factor (erythroid-derived 2)-like 2 (NRF2), which results in reduced expression of antioxidant proteins. Deletion of Nrf2 in the hearts of Sirt2-/- mice reversed protection after PO. Finally, treatment of mouse hearts with a specific SIRT2 inhibitor reduced cardiac size and attenuates cardiac hypertrophy in response to PO. These data indicate that SIRT2 has detrimental effects in the heart and plays a role in cardiac response to injury and the progression of cardiac hypertrophy, which makes this protein a unique member of the SIRT family. Additionally, our studies provide a novel approach for treatment of cardiac hypertrophy and injury by targeting SIRT2 pharmacologically, providing a novel avenue for the treatment of these disorders.

    1. Medicine

    An unexpected role of neutrophils in clearing apoptotic hepatocytes in vivo

    Luyang Cao, Lixiang Ma ... Jingsong Xu
    Research Article

    Billions of apoptotic cells are removed daily in a human adult by professional phagocytes (e.g. macrophages) and neighboring nonprofessional phagocytes (e.g. stromal cells). Despite being a type of professional phagocyte, neutrophils are thought to be excluded from apoptotic sites to avoid tissue inflammation. Here, we report a fundamental and unexpected role of neutrophils as the predominant phagocyte responsible for the clearance of apoptotic hepatic cells in the steady state. In contrast to the engulfment of dead cells by macrophages, neutrophils burrowed directly into apoptotic hepatocytes, a process we term perforocytosis, and ingested the effete cells from the inside. The depletion of neutrophils caused defective removal of apoptotic bodies, induced tissue injury in the mouse liver, and led to the generation of autoantibodies. Human autoimmune liver disease showed similar defects in the neutrophil-mediated clearance of apoptotic hepatic cells. Hence, neutrophils possess a specialized immunologically silent mechanism for the clearance of apoptotic hepatocytes through perforocytosis, and defects in this key housekeeping function of neutrophils contribute to the genesis of autoimmune liver disease.

    1. Medicine

    Loss of Ptpmt1 limits mitochondrial utilization of carbohydrates and leads to muscle atrophy and heart failure in tissue-specific knockout mice

    Hong Zheng, Qianjin Li ... Cheng-Kui Qu
    Research Article

    While mitochondria in different tissues have distinct preferences for energy sources, they are flexible in utilizing competing substrates for metabolism according to physiological and nutritional circumstances. However, the regulatory mechanisms and significance of metabolic flexibility are not completely understood. Here, we report that the deletion of Ptpmt1, a mitochondria-based phosphatase, critically alters mitochondrial fuel selection – the utilization of pyruvate, a key mitochondrial substrate derived from glucose (the major simple carbohydrate), is inhibited, whereas the fatty acid utilization is enhanced. Ptpmt1 knockout does not impact the development of the skeletal muscle or heart. However, the metabolic inflexibility ultimately leads to muscular atrophy, heart failure, and sudden death. Mechanistic analyses reveal that the prolonged substrate shift from carbohydrates to lipids causes oxidative stress and mitochondrial destruction, which in turn results in marked accumulation of lipids and profound damage in the knockout muscle cells and cardiomyocytes. Interestingly, Ptpmt1 deletion from the liver or adipose tissue does not generate any local or systemic defects. These findings suggest that Ptpmt1 plays an important role in maintaining mitochondrial flexibility and that their balanced utilization of carbohydrates and lipids is essential for both the skeletal muscle and the heart despite the two tissues having different preferred energy sources.