Vitamin osteocalcin

In bone, three proteins have been described which are vitamin K-dependent, osteocalcin (bone Gla protein), matrix Gla protein (MGP), and protein S. Osteocalcin is synthetized by osteoclasts, regulated by the active form of vitamin D, calcitriol. Its capacity to bind calcium needs a vitamin K-dependent y-carboxylation of three glutamic acid residues. The calcium binding capacity of osteocalcin indicates a possible role in bone mineralization, but its exact function is still unclear. However, it is widely used as a serum marker for bone mineralization. Protein S, mainly a coagulant, is also vitamin-K dependent and synthesized in the liver. Children with... 

This illness is mainly characterized by an age-related bone loss. The detection of osteocalcin in bone was the starting point for a series of studies on the role of vitamin K-dependent proteins in bone development and maintenance and on possible supplemantation therapies. Epidemiologic studies found differences in the risk of hip fractures depending on the dietary vitamin K... 

Supplementation with high doses of vitamin K1 (1 mg/day for 14 days) or MK-4 (45 mg/day) resulted in decreased levels of undercarboxylated osteocalcin and increase of bone formation markers and in a significant reduction in bone loss, respectively. Using such high doses, any kind of effects besides vitamin K can not yet be ruled out and have to be further elucidated by long term studies. An overview can be found in a review by Palacios [4]. 

In contrast to the formation and calcification of bones, vitamin K seems to lower the risk of aortic calcification. The mechanisms for these antagonistic effects is not known but a participation of osteocalcin (expressed in artherosclerotic plaques) as well as of matrix Gla protein (MGP) are discussed. In addition, the vitamin K epoxide reductase complex seems to be involved [5]. 

Treatment of pregnant women with warfarin can lead to fetal bone abnormalities (fetal warfarin syndrome). Two proteins are present in bone that contain y-carboxygluta-mate, osteocalcin and bone matrix Gla protein. Osteocalcin also contains hydroxyproHne, so its synthesis is dependent on both vitamins K and C in addition, its synthesis is induced by vitamin D. The release into the circulation of osteocalcin provides an index of vitamin D stams. 

A number of iron-containing, ascorbate-requiring hydroxylases share a common reaction mechanism in which hydroxylation of the substrate is linked to decarboxylation of a-ketoglutarate (Figure 28-11). Many of these enzymes are involved in the modification of precursor proteins. Proline and lysine hydroxylases are required for the postsynthetic modification of procollagen to collagen, and prohne hydroxylase is also required in formation of osteocalcin and the Clq component of complement. Aspartate P-hydroxylase is required for the postsynthetic modification of the precursor of protein C, the vitamin K-dependent protease which hydrolyzes activated factor V in the blood clotting cascade. TrimethyUysine and y-butyrobetaine hydroxylases are required for the synthesis of carnitine. 

Vitamin K promotes the hepatic y-car-boxylation of glutamate residues on the precursors of factors II, VII, IX, and X, as well as that of other proteins, e.g., protein C, protein S, or osteocalcin. Carboxyl groups are required for Ca +-mediat-ed binding to phospholipid surfaces (p, 142). There are several vitamin K derivatives of different origins Ichlorophyllous plants I<2 from gut bacteria and I<3 (menadione) synthesized chemically. All are hydrophobic and require bile acids for absorption. 

The mechanism of action of the vitamin D metabolites remains under active investigation. However, calcitriol is well established as the most potent agent with respect to stimulation of intestinal calcium and phosphate transport and bone resorption. Calcitriol appears to act on the intestine both by induction of new protein synthesis (eg, calcium-binding protein and TRPV6, an intestinal calcium channel) and by modulation of calcium flux across the brush border and basolateral membranes by a means that does not require new protein synthesis. The molecular action of calcitriol on bone has received less attention. However, like PTH, calcitriol can induce RANK ligand in osteoblasts and proteins such as osteocalcin, which may regulate the mineralization process. The metabolites 25(OH)D and 24,25(OH)2D are far less... 

The physiological role of vitamin K is in blood clotting and is essential for the synthesis of at least four of the proteins (including prothrombin) involved in this process. Vitamin K also plays a role in the synthesis of a protein (osteocalcin) in bone. Vitamin K deficiency is rare but can result from impaired absorption of fat. Vitamin K levels in the body are also reduced if the intestinal flora is killed (e.g. by antibiotics). Vitamin K toxicity is rare but can be caused by excessive intake of vitamin K supplements. Symptoms include erythrocyte haemolysis, jaundice, brain damage and reduced effectiveness of anticoagulants. 

More dramatical examples of conformational change have been reported for Ca2 + -binding proteins. Osteocalcin is an abundant Ca2+-binding protein characterized by the presence of the unique vitamin K-dependent y-carboxy glutamic acid ll5). The... 

Compounds with vitamin K activity (Table 6.2) are required in our diets for y-carboxyglutamate biosynthesis (Table 4.1). This amino acid is produced from certain protein glutamyl residues by carboxylation. Proteins that contain y-carboxyglutamate are blood prothrombin and coagulation factors VII, IX, and X (see Chapter 7). Other proteins of this type are osteocalcin from bone and several kidney and muscle calcium-binding proteins. 

Undercarboxylated osteocalcine is probably a result of the lack of vitamin K, and it can be its indicator (S10). On the contrary, decrease in affinity of the undercarboxylated osteocalcine to apatite can explain the ability to predict bone fractures (V5). 

Synthetic dihydro form (KH2) coenzyme for "y-carboxyglutamic acid formation on procagulant factors II, VII, IX, X, anticoagulant proteins C S, matrix Gla protein osteocalcin Synthetic cf. Dicoumarol, Vitamins K,K2 K3... 

Osteocalcin is induced in osteoblasts by calcitriol, and circulating osteocalcin can be used as an index of calcitriol action and metabolic bone disease. In rachitic children, the plasma concentration of osteocalcin is lower than in controls, and rises on therapy, remaining high until there is radiological evidence of cure. However, plasma osteocalcin can be undetectably low in normal subjects with adequate vitamin D status, so this does not provide a useful indication of deficiency (Greig et al., 1989). 

In deficiency, there is also undercarboxylated osteocalcin in the circulation, and this provides a more sensitive index of marginal status it is detectable, and responds to supplements of vitamin K, in subjects with normal clotting time and no circulating preprothrombin (Sokoll and Sadowski, 1996 Binkley et al., 2000). 

Lian JB, Stein GS, Stein JL, and van Wijnen AJ (1999) Regulated expression of the bone-specific osteocalcin gene by vitamins and hormones. Vitamins and Hormones 55, 443-509. 

Binkley NC, Krueger DC, Engelke JA, Eoley AL, and Snttie JW (2000) Vitamin K snpple-mentation reduces serum concentrations ofunder-gamma-carhoxylated osteocalcin in healthy young and elderly adults. American Journal of ClinicalNutrition72,1523-8. 

---