Gamma-carboxylation regulates osteocalcin function

The only well described function of vitamin K (VK) is to serve as a co-factor for the γ-carboxylation of particular proteins to convert specific glutamic acid (Glu) residues to γ-carboxyglutamic acid (Gla) residues. This process involves two enzymes, γ-glutamyl carboxylase (γ-carboxylase or GGCX) and vitamin K epoxide reductase (VKORC1), which together constitute the vitamin K cycle [1]. Physiologically, γ-carboxylation is known to be critical for the function of many coagulation factors (prothrombin, factor IX, factor VII, etc), but is also implicated in the regulation of Matrix Gla Protein (MGP) that inhibits extra-osseous tissue mineralization and of osteocalcin that regulates glucose metabolism. Osteocalcin is an osteoblast-derived γ-carboxylated protein present at high concentration in the bone extracellular matrix (ECM). Because Gla osteocalcin have great affinity for hydroxyapatite, the mineral component of bone ECM, it was originally believed to play a role in bone mineralization. Nevertheless, gain-and loss-of-function mouse models of osteocalcin have shown that this protein is not required for normal bone remodeling or mineralization [2]. Instead, the characterization of Ocn-/-mice revealed that osteocalcin is acting as a bone-derived hormone regulating glucose metabolism [3-4]. Cell culture and in vivo studies have shown that osteocalcin improves glucose handling by promoting insulin secretion by β-cells on one hand and by favouring insulin sensitivity on the other hand [1]. Although both the Gla and the Glu forms of osteocalcin are detected in the serum, the vast majority of the in vitro and in vivo studies conducted so far suggests that the endocrine function of osteocalcin is fulfilled by its Glu form. Interestingly, additional experiments involving the characterization of mice having either increased or decreased osteoclast number suggest that bone resorption is required to decarboxylate and release osteocalcin from the bone matrix [5-6]. Accordingly, many but not all studies in human have shown that serum levels of Glu osteocalcin negatively correlate with insulin resistance, obesity, diabetes or markers of the metabolic syndrome [1]. So far the data on osteocalcin endocrine regulation were supporting a model in which osteocalcin produced by osteoblasts is stored as a γ-carboxylated and inactive protein in the bone ECM, before being activated by decarboxylation during bone resorption. This model predicts that blocking osteocalcin γ-carboxylation would prevent osteocalcin accumulation in the bone ECM and thereby improve glucose homeostasis. In a recent study published in The Journal of Cell Biology [7] we tested directly this assumption aiming at providing direct evidence demonstrating that γ-carboxylation …