eLife (Dec 2020)

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

  • Omar Al Rifai,
  • Catherine Julien,
  • Julie Lacombe,
  • Denis Faubert,
  • Erandi Lira-Navarrete,
  • Yoshiki Narimatsu,
  • Henrik Clausen,
  • Mathieu Ferron

DOI
https://doi.org/10.7554/eLife.61174
Journal volume & issue
Vol. 9

Abstract

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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.

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