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

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.

Osteocalcin and the physiology of danger

“…Yet, probably the most critical consequence of the identification of Gprc6a as a receptor of osteocalcin has been to allow the study of the biology of osteocalcin in humans as will be described below. More broadly, it gave to osteocalcin a more complete hormonal identity, which has now been confirmed by numerous independent cell culture studies, in vivo studies in multiple species and multiple disease models, by correlative studies in humans and as we will describe, human genetic evidence [37,42,45–120]. It was also confirmed even more recently by the generation of a new genetic model of Osteocalcin deficiency [50].…”

“…It was also confirmed even more recently by the generation of a new genetic model of Osteocalcin deficiency [50]. While the evidence indicating that osteocalcin acts as a hormone in rodents and primates grows at an increasing pace, as the sample of references presented above indicates [37,42,45–120], this does not mean that there are no studies in which Osteocalcin ‐deficient mice were presented as normal [51].…”

Translational perspective on bone-derived cytokines in inter-organ communications

“…Recently, an interesting study published in eLife uncovered a novel O-glycosylation modification on a single serine (S8) of mouse OCN, which is essential to increase the stability of OCN in circulation, while the human OCN (hOCN) cannot be O-glycosylated as the corresponding amino acid residue is a tyrosine (Y12). 4 Moreover, they demonstrated that a single-point mutation (Y12S) is sufficient to mediate the O-glycosylate and then increase the half-life of hOCN ex vivo . These findings provide an explanation of the differences in circulation levels of OCN between humans and mice.…”

Osteocalcin Is Independently Associated with C-Reactive Protein during Lifestyle-Induced Weight Loss in Metabolic Syndrome

“…Osteocalcin is a noncollagenous protein secreted by osteoblasts, reflecting osteoblast activity [ 11 ]. Interestingly, osteocalcin knockout mice are characterized by an increase in visceral fat mass, as well as hyperglycemia, hypoinsulinemia, and reduced β-cell mass [ 12 ], indicating that osteocalcin regulates glucose metabolism and insulin secretion in mice [ 13 , 14 , 15 ]. Furthermore, administration of osteocalcin was shown to improve insulin sensitivity and to decrease the severity of obesity and T2DM in mice fed with a high-fat diet [ 14 ].…”