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The half-life of the bone-derived hormone osteocalcin is regulated through O-glycosylation in mice, but not in humans

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Cite this article as: eLife 2020;9:e61174 doi: 10.7554/eLife.61174

Abstract

Osteocalcin (OCN) is an osteoblast-derived hormone with pleiotropic physiological functions. Like many peptide hormones, OCN is subjected to post-translational modifications (PTMs) which control its activity. Here, we uncover O-glycosylation as a novel PTM present on mouse OCN and occurring on a single serine (S8) independently of its carboxylation and endoproteolysis, two other PTMs regulating this hormone. We also show that O-glycosylation increases OCN half-life in plasma ex vivo and in the circulation in vivo. Remarkably, in human OCN (hOCN), the residue corresponding to S8 is a tyrosine (Y12), which is not O-glycosylated. Yet, the Y12S mutation is sufficient to O-glycosylate hOCN and to increase its half-life in plasma compared to wildtype hOCN. These findings reveal an important species difference in OCN regulation, which may explain why serum concentrations of OCN are higher in mouse than in human.

Data availability

All the numerical data and the original western blots are available in the source data Excel file submitted with the manuscript. The raw proteomics data have been uploaded to a public server.

The following data sets were generated

Article and author information

Author details

  1. Omar Al Rifai

    Molecular Physiology, IRCM, Montreal, Canada
    Competing interests
    The authors declare that no competing interests exist.
  2. Catherine Julien

    Molecular Physiology, IRCM, Montreal, Canada
    Competing interests
    The authors declare that no competing interests exist.
  3. Julie Lacombe

    Molecular Physiology, IRCM, Montreal, Canada
    Competing interests
    The authors declare that no competing interests exist.
  4. Denis Faubert

    Proteomics Discovery Platform, IRCM, Montreal, Canada
    Competing interests
    The authors declare that no competing interests exist.
  5. Erandi Lira-Navarrete

    Copenhagen Center for Glycomics, Departments of Cellular and Molecular Medicine and School of Dentistry, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
    Competing interests
    The authors declare that no competing interests exist.
  6. Yoshiki Narimatsu

    Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark
    Competing interests
    The authors declare that no competing interests exist.
  7. Henrik Clausen

    Copenhagen Center for Glycomics, Departments of Cellular and Molecular Medicine and School of Dentistry, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
    Competing interests
    The authors declare that no competing interests exist.
  8. Mathieu Ferron

    Molecular Physiology, IRCM, Montreal, Canada
    For correspondence
    mathieu.ferron@ircm.qc.ca
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5858-2686

Funding

Canadian Institutes of Health Research (Operation fund,MOP-133652)

  • Mathieu Ferron

Canadian Institutes of Health Research (Project Operating fund,PJT-159534)

  • Mathieu Ferron

Natural Sciences and Engineering Research Council of Canada (Discovery grant,RGPIN-2016-05213)

  • Mathieu Ferron

Danmarks Grundforskningsfond (DNRF107)

  • Henrik Clausen

Fonds de Recherche du Québec - Santé (Doctoral scholarship)

  • Omar Al Rifai

Institut de Recherche Clinique De Montréal (Doctoral scholarship)

  • Omar Al Rifai

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 animal use complied with the guidelines of the Canadian Committee for Animal Protection and was approved by IRCM Animal Care Committee (protocol # 2016-14 MF).

Reviewing Editor

  1. Mone Zaidi, Icahn School of Medicine at Mount Sinai, United States

Publication history

  1. Received: July 16, 2020
  2. Accepted: December 6, 2020
  3. Accepted Manuscript published: December 7, 2020 (version 1)
  4. Version of Record published: January 22, 2021 (version 2)

Copyright

© 2020, Al Rifai 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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