Vitamin K is required for the biological activity of several coagulation factors including four procoagulants, factors II (prothrombin), VII, IX and X and two feedback anticoagulants, proteins C and S. A seventh plasma protein (Z) may have a haemostatic role but its function is currently unknown (Shearer, 2000). Specifically, vitamin K functions as a cofactor for vitamin K-dependent carboxylase, a microsomal enzyme that facilitates the post-translational conversion of glutamyl (Glu) residues in the protein precursor to g-carboxyglutamic acid (Gla). The biological relevance of the Gla structure is that it forms a cage structure to which divalent metal ions such as calcium may be bound (Berkner, 2000).
The synthesis of clotting factors occurs in the hepatic tissue. In its severest form, vitamin K deficiency results in bleeding syndrome due to lowering of circulating levels of the procoagulant factors and their replacement by under-carboxylated species.
Two vitamin K-dependent bone proteins were identified towards the end of the twentieth century. In 1975, it was found that bone tissue contains the Gla protein osteocalcin (BGP), which is one of the most abundant proteins in the body (Hauschka et al, 1975). In 1985 the matrix Gla protein, MGP, was discovered in bone, dentine and cartilage (Price, 1988). Osteocalcin is a water-soluble 49-residue protein and accounts for up to 80% of the total g-carboxyglutamyl content of mature bone (Olson, 1999). Its discovery changed the thinking about the role of vitamin K. Although the exact role of osteocalcin in bone metabolism is still not understood, the available data suggest a regulatory function of osteocalcin in bone mineral maturation (Weber, 2001). Osteocalcin is synthesised by osteoblasts and since its concentration in blood reflects osteoblast activity, measurement of total osteocalcin in blood has become accepted as a marker of bone turnover (Khosla and Kleerekoper, 1999). In addition, the extent to which osteocalcin is carboxylated is believed to be a more sensitive measure of vitamin K status than the conventional tests involving blood coagulation. High serum concentrations of undercarboxylated osteocalcin (ucOC) are indicators of low vitamin K status and vice versa (Weber, 2001).
Work during the 1980s using cultured osteosarcoma cells showed that osteocalcin and MGP are regulated by 1,25-OHD (Olson, 1999). However, more recent studies have demonstrated that retinoic acid receptors and vitamin D hormone receptors may form heterodimers that bind to the osteocalcin promoter in the cells allowing retinoic acid and 1,25-OHD to work synergistically in the cultured cells, i.e. osteocalcin and MGP may mediate some of the actions of vitamin D on bone. It has been shown that a deficiency of osteocalcin does not appear to affect repair of bone structure but in bone disease, plasma osteocalcin is elevated (Price, 1988). The author concluded that osteocalcin may stimulate bone remodelling and calcium mobilisation while MGP may be associated with the inhibition of growth-plate mineralisation.
There is evidence that vitamin K positively influences calcium balance, a key mineral in bone metabolism. Humans given a diet rich in vitamin K showed an increase in calcium retention within the body (Sakamoto et al, 1999). There is some evidence to suggest that proteins located in the kidney are responsive to vitamin K and that g-carboxy-glutamic acid may be involved in calcium retention and contribute to the effect.
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