Vitamin K and metabolic bone disease.
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Adult↗
Biomedical subjects
C Vermeer
Publications and source records attributed to C Vermeer.
Bone markers during a 6-month space flight: effects of vitamin K supplementation.
Rapid bone loss is a serious health problem for astronauts during long lasting missions in space. We have recorded the changes of biochemical markers for bone metabolism in one of the astronauts during the 6-month space flight of the EUROMIR-95 mission. Immediately after launch both bone resorption markers and urinary calcium excretion increased about two fold, whereas bone formation markers remained unchanged. After 12 1/2 weeks the astronaut received vitamin K1 (10 mg/day for 6 weeks). Vitamin K is known to be involved in the formation of gamma-carboxyglutamate (Gla) in proteins, such as the calcium-binding bone Gla-proteins osteocalcin and matrix Gla-protein. Concomitant with the start of vitamin K treatment, the calcium-binding capacity of osteocalcin increased, and so did the urinary excretion of free Gla. This is suggestive for a subclinical vitamin K-deficiency in the astronaut before vitamin K-supplementation. During periods of high vitamin K status markers for bone formation (osteocalcin and bone alkaline phosphatase) had increased as compared to the first part of the flight. The mean increases were 14 and 23%, respectively. Our data suggest that increased intake of vitamin K may contribute to counteracting microgravity-induced loss of bone mass during long lasting space missions, but need confirmation in more astronauts.
1-Carboxyglutamic Acid↗
Modulation of arterial thrombosis tendency in rats by vitamin K and its side chains.
Vitamin K is involved in the biosynthesis of a number of blood coagulation factors and bone proteins. It has been suggested that the vitamin K requirement of bone tissue is higher than that of the liver. Here we report that in rats very high doses of vitamin K affected neither the blood coagulation characteristics nor the blood platelet aggregation rate. This was observed for both phylloquinone and menaquinone-4. Both vitamers were also tested for their effects on the arterial thrombosis tendency in the rat aorta loop model. The mean obstruction times were prolonged at a high intake of menaquinone-4 (250 mg/kg body weight/day), and shortened after a similarly high phylloquinone regimen. Since (a) both vitamers only differ in their aliphatic side chains; and (b) a similar trend was observed after administration of phytol and geranylgeraniol, we conclude that the modulation of the arterial thrombosis tendency is accomplished by the side chain of vitamin K.
Animals↗
Nutritional vitamin K-intake and urinary gamma-carboxyglutamate excretion in the rat.
Using the rat as an experimental animal model we have found that prothrombin synthesis reaches its maximal level at a relatively low dietary vitamin K intake. At still higher vitamin K intakes, however, the urinary Gla-excretion was substantially increased, showing a different vitamin K requirement for liver and extrahepatic tissues. The increased urinary Gla-excretion was found for both phylloquinone and menaquinone-4, but not for menaquinone-8, which questions the bioavailability of higher menaquinones for extrahepatic tissues. A discrepancy was found between effects of nutritional vitamin K-deficiency and treatment with a vitamin K-antagonist (brodifacoum). With both regimens plasma prothrombin rapidly decreased to well below 10% of the starting values, but in case of K-deficiency urinary Gla had hardly decreased in 7 days, whereas after 3 days of brodifacoum treatment Gla-excretion had decreased to 17% of the starting values. An explanation for this observation is that prothrombin procoagulant activity does not decrease proportional to the prothrombin Gla-content, but that a wide range of undercarboxylated prothrombins have lost nearly all activity. During vitamin K-deficiency the remaining low levels of vitamin K would mainly give rise to undercarboxylated prothrombin, whereas during brodifacoum treatment only non-carboxylated prothrombin is formed. It seems plausible that in the latter case the urinary Gla originates from proteins with long half-life times, such as the bone Gla-proteins.
1-Carboxyglutamic Acid↗
Assay of vitamin K-dependent carboxylase activity in hepatic and extrahepatic tissues.
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Animals↗
Strategies for developing human osteocalcin standards: a critical evaluation.
Osteocalcin is a small protein uniquely produced by osteoblasts and odontoblasts. Since about 30% of the de novo synthesized osteocalcin is set free in the blood stream, it is widely used as a marker for bone formation. However, circulating immunoreactive osteocalcin (irOC) consists of several fractions, which may differ from each other with respect to size and calcium binding properties. Whereas it is generally assumed that the fraction with high affinity for hydroxyapatite reflects bone formation, we have found a high correlation between bone mass and irOC with low affinity for hydroxyapatite. Since the antibodies used in various commercial test kits for osteocalcin have different affinities for the various irOC fractions, well-defined homogenous standards have to be prepared which may be used for standardization of the detection techniques used in various laboratories. In this paper we give a critical evaluation of the strategies which may be followed.
Amino Acid Sequence↗
Osteocalcin detection in aging serum and whole blood: stability of different osteocalcin fractions.
Human serum osteocalcin is a well known bone formation marker. On the basis of their different affinities for hydroxyapatite, the total immunoreactive osteocalcin may be separated into two fractions. Six commercial test kits for osteocalcin were compared. All kits reacted with both osteocalcin fractions but the absolute amounts found in the same serum samples differed widely. During serum storage at room temperature, there was no significant loss of osteocalcin during the first 6 h. After longer storage periods, the recorded decrease of osteocalcin depended on the system used: with two kits, over 80% of the original immunoreactive antigen was left after 9 days. It is considered that the different osteocalcin fractions may become useful as markers for different metabolic bone processes. A more precise definition of the various circulating osteocalcin fractions, and the development of separate tests for each fraction, are requirements for the optimal use of osteocalcin as a diagnostic tool for metabolic bone disorders.
Adult↗
Natural prenylquinones inhibit the enzymes of the vitamin K cycle in vitro.
Vitamin K belongs to a class of compounds commonly known as prenylquinones. Three other prenylquinones which are abundantly found in food are plastoquinone-9, ubiquinone-9 and ubiquinone-10. Using in vitro assay systems, it was recently found that synthetic derivatives of prenylquinones inhibit the vitamin K-dependent enzyme gamma-glutamylcarboxylase and, to a lesser extent, the vitamin K-epoxide reductase. In this paper we describe how natural prenylquinones affect the vitamin K-dependent enzymes in vitro. All three prenylquinones were found to inhibit both the vitamin K-dependent carboxylase and the K-epoxide reductase in a rat as well as in a cow liver system; 50% inhibition was obtained at concentrations in the micromolar range. On the basis of their respective standard redox potentials, a possible mechanism for the inhibitory effect of prenylquinones on the carboxylase enzyme is put forward. It is concluded that natural prenylquinones are potential antagonists of vitamin K and may interfere with vitamin K-dependent reactions in vivo.
Animals↗
Vitamin K status and bone mass in women with and without aortic atherosclerosis: a population-based study.
Gammacarboxyglutamate (Gla) is an uncommon amino acid formed by vitamin K action. Increasing evidence indicates that Gla-proteins are involved in the regulation of calcification processes in both bone tissue and atherosclerotic vessel wall. In a population-based study we have previously shown that in a group of 113 postmenopausal women the presence of abdominal aortic calcifications is associated with a reduced vitamin K status. In the present study we investigated whether this reduced vitamin K status was also associated with differences in bone mass or circulating calciotropic hormone levels. Serum immunoreactive osteocalcin with low affinity for hydroxyapatite (irOCfree) was used as a marker for vitamin K status. After correction for age it was found that women with atherosclerotic calcifications had a 7% lower bone mass as measured by metacarpal radiogrammetry (mean difference: 3.2 mm2, 95% CI: -0. 2-6.5, P = 0.06). No differences between both groups of women were observed for serum intact parathyroid hormone (PTH) and serum 25-hydroxyvitamin D levels. In the atherosclerotic women (n = 34), markers for vitamin K status were inversely associated with bone mass (r = -0.47, P = 0.013), whereas no such association was found in the nonatherosclerotic women (n = 79). It is concluded that the atherosclerotic women in this study may be at higher risk for osteoporotic fractures as evidenced by their lower bone mass and higher serum irOCfree levels. The finding that in atherosclerotic women vitamin K status is associated with bone mass supports our hypothesis that vitamin K status affects the mineralization processes in both bone and in atherosclerotic plaques.
Aged↗
Effect of food composition on vitamin K absorption in human volunteers.
The human vitamin K requirement is not known precisely, but the minimal requirement is often assumed to be between 0.5 and 1 x 10(-6) g/kg body weight. In the present study we addressed the question to what extent circulating vitamin K concentrations are influenced by the form in which the vitamer is consumed. The experimental group consisted of five healthy volunteers who received phylloquinone after an overnight fast. On the first day of three successive weeks the participants consumed 1 mg (2.2 mumol) phylloquinone, either in the form of a pharmaceutical preparation (Konakion), or in the form of spinach + butter, or as spinach without added fat. Circulating phylloquinone levels after spinach with and without butter were substantially lower (7.5- and 24.3-fold respectively) than those after taking the pharmaceutical concentrate. Moreover, the absorption of phylloquinone from the vegetables was 1.5 times slower than from Konakion. In a second experiment in the same five volunteers it was shown that relatively high amounts of menaquinone-4 enter the circulation after the consumption of butter enriched with this vitamer. It is concluded that the bioavailability of membrane-bound phylloquinone is extremely poor and may depend on other food components, notably fat. The bioavailability of dietary vitamin K (phylloquinone + menaquinones) is lower than generally assumed, and depends on the form in which the vitamin is ingested. These new insights may lead to a revision of the recommended daily intake for vitamin K.
Adult↗
Effects of vitamin K on bone mass and bone metabolism.
Vitamin K is involved in blood coagulation and in bone metabolism via the carboxylation of glutamate residues in (hepatic) blood coagulation factors and (osteoblastic) bone proteins. The bioavailability of nutritional vitamin K depends on the type of food, the dietary fat content, the length of the aliphatic side chain in the K-vitamer and probably also the genetically determined polymorphism of apolipoprotein E. Although undercarboxylation of blood coagulation factors is very rare, undercarboxylated osteocalcin (bone Gla-protein) is frequently found in postmenopausal women. Supplementation of these women with extra vitamin K causes the markers for bone formation to increase. In parallel, a decrease of the markers for bone resorption is frequently seen. Insufficient data are available to conclude that the regular administration of vitamin K concentrates will reduce the loss of bone mass in white women at risk for developing postmenopausal osteoporosis.
Animals↗
Potential effect of vitamin K on microgravity-induced bone loss.
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Administration, Oral↗
Bioavailability of phylloquinone and menaquinones after oral and colorectal administration in vitamin K-deficient rats.
Rats were made vitamin K-deficient by feeding them a diet devoid of vitamin K and by rigorously preventing coprophagy. After one week, circulating prothrombin concentrations were between 5 and 10% of initial values, and various amounts of phylloquinone, menaquinone-4, and menaquinone-9 were given in a single dose either subcutaneously, orally, or colorectally. The relative 'vitamin K activities' of these compounds were assessed by comparing their ability to support prothrombin synthesis after subcutaneous injection. Intestinal and colonic absorption were deduced from the difference between subcutaneous and either oral or colorectal administration of the vitamers. It is concluded that the colonic absorption of all three forms of vitamin K is extremely poor, suggesting that physiological menaquinones in the colon do not contribute substantially to vitamin K status in rats. Furthermore, the stimulation of prothrombin synthesis by menaquinone-9 lasted much longer than that by the two other K-vitamers, resulting in a substantially higher 'vitamin K activity' of menaquinone-9.
Animals↗
[Vitamin K: current viewpoints in connection with bone metabolism].
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Biomarkers↗
A specific colorimetric staining method for gamma-carboxyglutamic acid-containing proteins in polyacrylamide gels.
In this paper we describe a specific staining method for gamma-carboxyglutamic acid (Gla)-containing proteins in polyacrylamide gels. The procedure is based on the colorimetric detection of Gla using 4-diazobenzenesulfonic acid and has the advantage of being simple and fast (1 h). The detection limit is 9.4 pmol for prothrombin and 150 pmol for osteocalcin. It is demonstrated that Gla-proteins can be visualized independent of the presence of an excess of contaminating non-Gla-proteins. The technique may be used for screening of large number of fractions during the purification of Gla-proteins from complex protein mixtures.
1-Carboxyglutamic Acid↗
Vitamin K intake and osteocalcin levels in women with and without aortic atherosclerosis: a population-based study.
Protein-bound gamma-carboxyglutamate (Gla) has been demonstrated in calcified atherosclerotic plaques. Vitamin K is required for the formation of Gla-residues. As the biological activity of Gla-proteins appears to be strictly dependent on the presence of the Gla-residues, vitamin K status may be an important factor in the development and progression of atherosclerotic calcifications. We studied the association of vitamin K status, as assessed by nutritional vitamin K intake and the measurements of two circulating immunoreactive osteocalcin (irOC) fractions, with aortic atherosclerosis in a population-based study of 113 postmenopausal women. Women with calcified lesions (n = 34) had a 42.9 micrograms lower mean age-adjusted dietary vitamin K intake/day (95% C.I. -6.6 to 92.5) than those without calcifications (n = 79). Atherosclerotic women had higher irOC levels with a low affinity for hydroxyapatite (irOCfree): age-adjusted difference of 0.32 ng/ml (95% C.I. 0.03 to 0.61). In addition, the high affinity irOC levels expressed as a percentage (hydroxyapatite binding capacity, HBC) were 5.12% (95% C.I. 1.32 to 8.92) lower in women with calcifications. Our study indicates that women with aortic atherosclerosis have an impaired vitamin K status as reflected by a lower nutritional vitamin K intake, an increased irOCfree level and a reduced HBC level. An impaired vitamin K status in subjects with atherosclerosis is compatible with the view that vitamin K or Gla-containing proteins are involved in the development of calcification of the vessel wall.
1-Carboxyglutamic Acid↗
Role of vitamin K in bone metabolism.
Vitamin K is a cofactor required for the formation of gamma-carboxyglutamate (Gla) residues in proteins. Osteoblasts produce at least three different Gla-containing proteins: osteocalcin, matrix Gla-protein, and protein S. After cellular secretion of these proteins, the main part of each remains bound to the hydroxyapatite matrix in bone, but their function remains unclear. Part of the newly synthesized osteocalcin is also set free into the bloodstream, where it may be used as a diagnostic marker for bone formation. Several studies have demonstrated that a poor vitamin K status is associated with an increased risk of osteoporotic bone fractures. Whether vitamin K supplementation will reduce the rate of bone loss in postmenopausal women remains a matter of debate.
Animals↗
Vitamin K-antagonistic effect of plastoquinone and ubiquinone derivatives in vitro.
Decyl-ubiquinone and decyl-plastoquinone were used as model compounds to test the potential effect of quinone derivatives on two enzymes of the vitamin K cycle in vitro. Substantial inhibition of gamma-glutamate carboxylase was found, whereas vitamin K-epoxide reductase was inhibited to a much lesser extent. The inhibitory effect of both decylquinones was eliminated in a time-dependent way by solubilized microsomes, but not by purified carboxylase. Since a wide variety of prenylquinones occur as micronutrients, these results are of potential relevance for the effects of natural quinones in the human diet.
Animals↗