The role of osteocalcin in human glucose metabolism: marker or mediator?

Abstract

Increasing evidence supports an association between the skeleton and energy metabolism. These interactions are mediated by a variety of hormones, cytokines and nutrients. Here, the evidence for a role of osteocalcin in the regulation of glucose metabolism in humans is reviewed. Osteocalcin is a bone matrix protein that regulates hydroxyapatite size and shape through its vitamin-K-dependent, γ-carboxylated form. The concentration of osteocalcin in the circulation is a measure of bone formation. The undercarboxylated form of osteocalcin is active in glucose metabolism in mice. Total serum osteocalcin concentrations in humans are inversely associated with measures of glucose metabolism; however, human data are inconclusive with regard to the role of uncarboxylated osteocalcin in glucose metabolism because most studies do not account for the influence of vitamin K on the proportion of undercarboxylated osteocalcin or differentiate between the total and uncarboxylated forms of osteocalcin. Furthermore, most human studies do not concomitantly measure other bone turnover markers to isolate the role of osteocalcin as a measure of bone formation from its effect on glucose metabolism. Carefully designed studies are required to define the role of osteocalcin and its carboxylated or undercarboxylated forms in the regulation of glucose metabolism in humans.

Figure 1

Vitamin K is required for the formation of γ-carboxyglutamic acid. γ-carboxyglutamic acid (Gla) is a unique amino acid that is created by a vitamin K-dependent post-translational modification of specific glutamic acid residues in all Gla-containing proteins, including osteocalcin. This process is inhibited by warfarin.

Figure 2

Direct structural analysis of osteocalcin by NMR imaging and X-ray crystallography predict a tight globular structure comprised of three α-helices, a C-terminal hydrophobic core and an unstructured N-terminus. All three γ-carboxyglutamic acid (Gla) residues are found in the first helical region. Osteocalcin amino acid sequences from all species share extensive amino homology at the central region containing the γ-carboxyglutamic acids but there is considerable sequence variation in other regions. The γ-carboxyglutamic acid residues are complementary to the calcium ions on the c-axis of the hydroxyapatite crystal lattice, and are positioned to control crystal size and shape within the constraints of the collagen fibril.

Figure 3

Response of all forms of osteocalcin to vitamin K supplementation in humans2-year changes(mean±SEM) in a ∣ serum total osteocalcin, b ∣ serum undercarboxylated osteocalcin and c ∣ percentage undercarboxylated osteocalcin in 396 men and women (age range 60–80 years) in response to 500 μg per day of vitamin K in the form of phylloquinone or no vitamin Ksupplementation (control) in a randomized, double-blind clinical trial. 2-year changes in total osteocalcin concentrations did not differ between groups. By contrast, vitamin K supplementation decreased concentrations of undercarboxylated osteocalcin and percent undercarboxylated osteocalcin in the phylloquinone group (P<0.05) but not in the control group, which demonstrates the need for vitamin K status to be considered when discussing the role of undercarboxylated osteocalcin in energy metabolism in humans. Abbreviations: OC, osteocalcin; ucOC, undercarboxylated osteocalcin. VK, vitamin K

Figure 4

Correlation among osteocalcin measures. a ∣ Serum undercarboxylated osteocalcin is highly correlated with total serum concentrations of osteocalcin whereas b ∣ the serum percentage of undercarboxylated osteocalcin is not correlated to total serum concentrations of osteocalcin. The 426 men and women who participated were community-based older adults (age range 60–80 years) free of osteoporosis and cardiovascular disease at the time of enrolment in a randomized double-blind clinical trial examining the effect of vitamin K supplementation on bone health. Osteocalcin measures were made prior to vitamin K supplementation. Abbreviations: OC, osteocalcin; ucOC, undercarboxylated osteocalcin.

Figure 5

in human circulation would be the consequence of two separate processes: incomplete carboxylation of osteocalcin due to suboptimal vitamin K intake or decarboxylation during osteoclast resorption. Insulin signalling in osteoblasts limits production of osteoprotegerin, an inhibitor of osteoclast maturation. This facilitates osteoclast bone resorption, producing an acid environment that decarboxylates, and hence activates intact osteocalcin. OST-PTP/PTN 1+2 dephosphorylates the insulin receptor (insR) in osteoblasts leading to inhibition of insulin signaling. Abbreviations: cOC, carboxylated osteocalcin. OPG, osteoprotegerin. ucOC undercarboxylated osteocalcin