Matrix Gla-protein: The calcification inhibitor in need of vitamin K

VitaK, Maastricht University, Universiteitssingel 50, Maastricht, The Netherlands.
Thrombosis and Haemostasis (Impact Factor: 4.98). 11/2008; 100(4):593-603. DOI: 10.1160/TH08-02-0087
Source: PubMed


Among the proteins involved in vascular calcium metabolism, the vitamin K-dependent matrix Gla-protein (MGP) plays a dominant role. Although on a molecular level its mechanism of action is not completely understood, it is generally accepted that MGP is a potent inhibitor of arterial calcification. Its pivotal importance for vascular health is demonstrated by the fact that there seems to be no effective alternative mechanism for calcification inhibition in the vasculature. An optimal vitamin K intake is therefore important to maintain the risk and rate of calcification as low as possible. With the aid of conformation-specific antibodies MGP species in both tissue and the circulation have been detected in the healthy population, and significant differences were found in patients with cardiovascular disease (CVD). Using ELISA-based assays, uncarboxylated MGP (ucMGP) was demonstrated to be a promising biomarker for cardiovascular calcification detection. These assays may have potential value for identifying patients as well as apparently healthy subjects at high risk for CVD and/or cardiovascular calcification and for monitoring the treatment of CVD and vascular calcification.

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Available from: Leon J Schurgers
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    • "MGP [matrix Gla (-carboxyglutamate) protein] is a circulating natural calcification inhibitor secreted primarily by chondrocytes and vascular smooth muscle cells in the arterial tunica media [1] [2]. Vitamin K plays a crucial role in its synthesis, serving as co-factor for the enzyme -glutamate carboxylase that converts glutamate residues into -carboxyglutamate (Gla) [3]. The anti-calcemic properties of MGP depend on its five Gla-residues serving as calcium-binding groups, while posttranslational phosphorylation of three serine residues was reported to enhance its cellular secretion [4] [5] Both transformation steps take place during maturation of MGP, but also incompletely carboxylated and phosphorylated MGP species are found in the circulation. "
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    ABSTRACT: Background: Matrix Gla protein (MGP) is a natural inhibitor of tissue calcification. In a previous study, we observed the positive association between abnormal concentrations of uncarboxylated MGP species and increased mortality risk in stable vascular patients. We explore whether co-incidence of abnormal status of uncarboxylated MPG and heart failure (HF) affects the mortality risk. Methods: We examined 799 patients (mean age 65.1years) with stable vascular disease and followed them in a prospective study. Both, desphospho-uncarboxylated and total uncarboxylated MGP (dp-ucMGP or t-ucMGP) were quantified by pre-commercial ELISA assays. Results: Elevated (>100ng/L) circulating brain natriuretic peptide (BNP) and abnormal status of plasma uncarboxylated MGP species (i.e.: dp-ucMGP ≥977pmol/L or t-ucMGP≤2825nmol/L) were all identified as robust predictors of all-cause 5-year mortality. However, their co-incidence represented a substantial additional risk. We observed the highest mortality risk in patients with elevated BNP plus high dp-ucMGP compared to those with normal BNP plus low dp-ucMGP; fully adjusted HRR's were 4.86 (3.15-7.49). Likewise, the risk was increased when compared with patients with elevated BNP plus low dp-ucMGP; HRR 2.57 (1.60-4.10). Similar result we observed when co-incidence of elevated BNP and low t-ucMGP was analyzed [corresponding HRR's were 4.16 (2.62-6.61) and 1.96 (1.24-3.12)]. Conclusions: The concomitant abnormality of uncarboxylated MGP and mild elevation of BNP leads in chronic patients with vascular disease to about two-fold increase of the relative mortality risk. We hypothesize that abnormal homeostasis of MGP is involved in the pathophysiology of HF.
    Full-text · Article · Oct 2015 · International journal of cardiology
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    • "En effet, plusieurs e ´ tudes ont dé montré que les concentrations de dp-ucMGP augmentent significativement chez les patients traité s par anti-vitamine K (AVK) [27,36,44–47] et, inversement, diminuent aprè s initiation d'un traitement par vitamine K, y compris dans le contexte de la maladie ré nale chronique (MRC) [27] [36] [46] [48]. Certaines donné es, nous y reviendrons, suggè rent une association positive entre les concentrations de dp-ucMGP et l'intensité des calcifications vasculaires (plus il y a de MGP inactive, plus il y a de risque de calcifications). "
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    ABSTRACT: Matrix-gla-protein (MGP) is mainly secreted by chondrocytes and smooth vascular muscle cells. This potent inhibitor of vascular calcification need to undergo 2 post-transcriptional steps to be fully active: one phosphorylation of 3 serine residues (on 5) and a carboxylation of 5 glutamate residues (on 9). Like other "Gla" proteins, this carboxylation is vitamin K dependant. Several forms of MGP thus circulate in the plasma, some of them being totally inactive (the unphosphorylated and uncarboxylated MGP), some others being partially or fully active, according to the number of phosphorylated or carboxylated sites. A theoretical link exists between MGP, vitamin K, vascular calcifications and cardiovascular diseases. This link is even more evident in patients suffering from chronic kidney diseases (CKD), and notably hemodialysis patients. If this link has been demonstrated in different experimental studies, clinical studies are mainly observational and their results must be interpreted accordingly. MGP concentrations are definitely not yet a surrogate to estimate the levels of vascular calcification, but could allow the monitoring of vitamin K treatment. Modulation of MGP concentrations may reduce vascular calcification in hemodialyzed patients, if the large ongoing trials show an efficiency of this treatment. In this review, we will summarize the role of MGP in the vascular calcifications process, describe the problems linked to the analytical determination of MGP in plasma and finally describe the different clinical studies on MGP and vascular calcifications in the general population and in CKD patients. Copyright © 2015 Association Société de néphrologie. Published by Elsevier SAS. All rights reserved.
    Full-text · Article · Mar 2015 · Néphrologie & Thérapeutique
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    • "Even if MMP-9 was also decreased, statistical significance was not reached. MMP-9 is localized in VSMCs (Woodside et al 2003) which also represent the site of MGP synthesis (Schurgers et al 2008). It seems possible that these findings could be the consequence of the surgical removal of VV, resulting in a decrease of venous tissue and therefore of VSMCs. "
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    ABSTRACT: Objectives: The main objective was to assess the interplay between circulating matrix Gla protein (MGP) - marker for vascular calcification, matrix metalloproteinase-9 (MMP-9) - marker for extracellular matrix remodeling and nitrotyrosine (NT) - marker for oxidative stress in patients with varicose veins (VV). Moreover, we wanted to investigate the behavior of these parameters before and after a stressful event (surgical removal of VV from lower limbs) and to find out if there is a contribution of MGP originating from superficial veins of the lower limb to the total pool of circulating MGP. Material and method: The pilot cohort study was accomplished on patients with VV (n=29) before and after a stressful event (surgical removal of VV from inferior limbs) and a group of age-gender matched apparently healthy volunteers (n=29). Plasma levels of tMGP, MMP-9 and NT were assayed with commercially available immunoassay kits. Results: Differences between patients with VV and age-sex matched healthy subjects were reflected only by higher levels of MMP-9 [82 (19-159) ng/mL versus 36 (2-108) ng/mL, p<0.05]; and not by circulating tMGP or NT levels. When patients before removal of VV were compared to patients after surgery, only tMGP was found significantly decreased [65 (32-97) μg/L versus 40 (17-95) μg/L, p<0.05]. We also found a correlation between tMGP and MMP-9 in patients with VV (r = 0.37, p<0.05). We did not find any correlation of NT with tMGP or MMP-9 and no significant differences in plasma NT levels in any pairwise comparisons. Conclusion: Higher circulating levels of MMP-9 could differentiate between healthy individuals and patients with chronic venous insufficiency. Consequently, oxidative stress assessed by NT did not affect circulating levels of tMGP or MMP-9 after surgical removal of VV. The constitutive decrease in plasma level of tMGP could be considered the contribution of MGP from superficial veins of the inferior limb to the total pool of circulating MGP
    Full-text · Article · Feb 2015 · Human and Veterinary Medicine
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