Over the past 20 years, several additional proteins that are unrelated to coagulation were identified as requiring this same vitamin K–dependent posttranslational modification. These VKD proteins seem to have a variety of physiologic roles in bone metabolism, vascular repair, preventing vascular calcification, cell-cell adhesion, cell cycle regulation, and signal transduction.Relative to bone, there are 3 known VKD proteins: OC, matrix Gla protein, and protein S.
Osteocalcin (OC) is a non-collagenous, Vitamin K-dependent protein secreted in the late stage of osteoblasts differentiation.
The presence of the three residues of γ-carbossiglutamatic acid, specific of the active form of OC protein, allows the protein to bind calcium and consequently hydroxyapatite.
OC is exclusively synthesized by osteoblasts and odontoblasts.OC is a low-molecular-weight protein made up of 47–50 amino acids, with human OC having 49 amino acids.
Its amino acid sequence (primary structure) has been highly conserved during evolution, and it is the most abundant noncollagenous protein in the bones and dentine of vertebrates.6,90 There are 3 Glu residues at positions 17, 21, and 24 that can be posttranslationally modified to Gla residues. The vitamin K–dependent enzyme γ-carboxylase catalyzes this γ-carboxylation. Although the precise role of OC in bone metabolism is not fully understood, a number of findings suggest its importance in regulating bone mineralization, maturation, and remodeling. The Gla residues in OC confer calcium ion binding, which is abolished when the Gla residues are decarboxylated to Glu residues.
The Gla residues in OC have a much greater affinity for hydroxyapatite (the mineral complex of bone, Ca106(OH)2) than for ionic calcium, and the spacing of the Gla residues corresponds to the spacing of calcium ions within the hydroxyapatite lattice. Furthermore, decarboxylation of Gla residues in OC sharply decreases its affinity for hydroxyapatite in vitro.Similarly, in animals treated with warfarin, non–γ-carboxylated OC is synthesized, which does not bind strongly to hydroxyapatite and does not appreciably accumulate in bone.
These characteristics of OC suggest that it is important in regulating mineralization and the formation of the calcium hydroxyapatite crystals of bone.Even if data obtained in literature are controversial, the dual role of OC in bone can be presumed as follows: firstly, OC acts as a regulator of bone mineralization; secondly, OC regulates osteoblast and osteoclast activity.
Recently the metabolic activity of OC, restricted to the un-carboxylated form has been demonstrated in osteoblast-specific knockout mice. This effect is mediated by the regulation of pancreatic β-cell proliferation and insulin secretion and adiponectin production by adipose tissue and leads to the regulation of glucose metabolism and fat mass. Nevertheless clinical human studies only demonstrated the correlation between OC levels and factors related to energy metabolism. Thus further investigations in humans are required to demonstrate the role of OC in the regulation of human energy metabolism. Moreover it is presumable that OC also acts on blood vessels by inducing angiogenesis and pathological mineralization.