The half-life of the bone-derived hormone osteocalcin is regulated through O-glycosylation in mice, but not in humans
- IRCM, Canada
- University of Copenhagen, Denmark
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.
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MS raw files for The half-life of the bone-derived hormone osteocalcin is regulated through O-glycosylation in mice, but not in humansFigshare, https://doi.org/10.6084/m9.figshare.13259891.v1.
Article and author information
Author details
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.
Reviewing Editor
- Mone Zaidi, Icahn School of Medicine at Mount Sinai, United States
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).
Version history
- Received: July 16, 2020
- Accepted: December 6, 2020
- Accepted Manuscript published: December 7, 2020 (version 1)
- 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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The half-life of the bone-derived hormone osteocalcin is regulated through O-glycosylation in mice, but not in humans
eLife 9:e61174.
https://doi.org/10.7554/eLife.61174
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