The Circulating Inactive Form of Matrix Gla Protein (ucMGP) as a Biomarker for Cardiovascular Calcification

Cranenburg, Ellen C. M.; Vermeer, Cees; Koos, Ralf; Boumans, Marie-Louise; Hackeng, Tilman M.; Bouwman, Freek G.; Kwaijtaal, Martijn; Brandenburg, Vincent; Ketteler, Markus; Schurgers, Leon J.

doi:10.1159/000124863

Cited by 161 publications

(156 citation statements)

References 76 publications

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“…The median ucMGP level was 4708 nM (range 2031-9603 nM). This is comparable to that of a healthy nonhypertensive reference population (4976 nM; 2685-8187) [22]. The median OCR was 1AE2 (0AE1-14AE0), which suggests a relatively low vitamin K status in these patients [24].…”

Section: Resultssupporting

confidence: 71%

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Calcium scores and matrix Gla protein levels: association with vitamin K status

Rennenberg

Leeuw

Kessels

et al. 2010

Eur J Clin Investigation

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Background Vascular calcification in humans is associated with an increased cardiovascular risk. Carboxylated matrix Gla protein (cMGP) inhibits vascular calcification. Vitamin K is an essential cofactor for the activation of uncarboxylated matrix Gla protein (ucMGP). It has been suggested that patients on long-term treatment with vitamin K antagonists develop aortic valve calcifications because of lower levels of circulating MGP. We therefore hypothesized that arterial calcification and a low vitamin K status are associated with ucMGP. To that aim, we measured arterial calcium scores, the osteocalcin ratio (OCR), as a proxy for vitamin K status, and ucMGP.

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Section: Resultssupporting

confidence: 71%

“…Previously, only reports showing a correlation of low serum unphosphorylated MGP and ucMGP levels in populations with increased cardiovascular risk have been published [22,28]. Phosphorylation of MGP is the first step in its activation and is induced by the presence of calcium.…”

Section: Discussionmentioning

confidence: 99%

Calcium scores and matrix Gla protein levels: association with vitamin K status

Rennenberg

Leeuw

Kessels

et al. 2010

Eur J Clin Investigation

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“…Reduced levels in patients with cardiovascular disease and CKD patients 31 Negative association with coronary calcification in dialysis patients 32 May be partially bioactive Low circulating levels reflect cardiovascular calcifications, possibly because of binding to vascular calcium precipitates dp-ucMGP (nonphosphorylated, uncarboxylated MGP)…”

Section: Mgp Species Studies Interpretationmentioning

confidence: 99%

Circulating Nonphosphorylated Carboxylated Matrix Gla Protein Predicts Survival in ESRD

Schlieper¹,

Westenfeld²,

Krüger³

et al. 2011

Journal of the American Society of Nephrology

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The mechanisms for vascular calcification and its associated cardiovascular mortality in patients with ESRD are not completely understood. Dialysis patients exhibit profound vitamin K deficiency, which may impair carboxylation of the calcification inhibitor matrix gla protein (MGP). Here, we tested whether distinct circulating inactive vitamin K-dependent proteins associate with all-cause or cardiovascular mortality. We observed higher levels of both desphospho-uncarboxylated MGP (dp-ucMGP) and desphospho-carboxylated MGP (dp-cMGP) among 188 hemodialysis patients compared with 98 agematched subjects with normal renal function. Levels of dp-ucMGP correlated with those of protein induced by vitamin K absence II (PIVKA-II; r ϭ 0.62, P Ͻ 0.0001). We found increased PIVKA-II levels in 121 (64%) dialysis patients, indicating pronounced vitamin K deficiency. Kaplan-Meier analysis showed that patients with low levels of dp-cMGP had an increased risk for all-cause and cardiovascular mortality. Multivariable Cox regression confirmed that low levels of dp-cMGP increase mortality risk (all-cause: HR, 2.2; 95% CI, 1.1 to 4.3; cardiovascular: HR, 2.7; 95% CI, 1.2 to 6.2). Furthermore, patients with higher vascular calcification scores showed lower levels of dp-cMGP. In 17 hemodialysis patients, daily supplementation with vitamin K2 for 6 weeks reduced dp-ucMGP levels by 27% (P ϭ 0.003) but did not affect dp-cMGP levels. In conclusion, the majority of dialysis patients exhibit pronounced vitamin K deficiency. Lower levels of circulating dp-cMGP may serve as a predictor of mortality in dialysis patients. Whether vitamin K supplementation improves outcomes requires further study. 22: 387-395, 201122: 387-395, . doi: 10.1681 Dialysis patients show an increased total and cardiovascular mortality. 1 Cardiovascular calcifications are well-established mortality predictors in ESRD patients. 2 Calcification is not only a passive but an actively regulated process dependent on calcification inhibitors. 3 Fetuin-A, a liver-derived protein, acts as a systemic calcification inhibitor, 4 and low serum levels have been shown to predict mortality in dialysis patients. 5 Matrix gla protein (MGP) is produced by vascular smooth muscle cells and acts locally in the vascular wall. 6 MGP can be modified by ␥-glutamate carboxylation and serine phosphorylation. The function of phosphorylation is not yet known, but recent data suggest that it plays a role in regulating the secretion of proteins into the extracellular environ- J Am Soc Nephrol

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“…For measurement of the total fraction of uncarboxylated MGP (ucMGP), a competitive ELISA assay was applied. 23,24 Two additional sandwich ELISAs were developed at VitaK BV, Maastricht, The Netherlands, to determine the respective plasma levels of desphospho carboxylated (dp-cMGP) or desphospho uncarboxylated (dp-ucMGP) MGP. In brief, monoclonal anti-dpMGP was coated to the microtiter plate.…”

Section: Biochemical Measurementsmentioning

confidence: 99%

Low serum vitamin K in PXE results in defective carboxylation of mineralization inhibitors similar to the GGCX mutations in the PXE-like syndrome

Vanakker

Martin

Schurgers

et al. 2010

Laboratory Investigation

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Soft-tissue mineralization is a tightly regulated process relying on the activity of systemic and tissue-specific inhibitors and promoters of calcium precipitation. Many of these, such as matrix gla protein (MGP) and osteocalcin (OC), need to undergo carboxylation to become active. This post-translational modification is catalyzed by the gammaglutamyl carboxylase GGCX and requires vitamin K (VK) as an essential co-factor. Recently, we described a novel phenotype characterized by aberrant mineralization of the elastic fibers resulting from mutations in GGCX. Because of the resemblance with pseudoxanthoma elasticum (PXE), a prototype disorder of elastic fiber mineralization, it was coined the PXE-like syndrome. As mutations in GGCX negatively affect protein carboxylation, it is likely that inactive inhibitors of calcification contribute to ectopic mineralization in PXE-like syndrome. Because of the remarkable similarities with PXE, we performed a comparative study of various forms of VK-dependent proteins in serum, plasma (using ELISA), and dermal tissues (using immunohistochemistry) of PXE-like and PXE patients using innovative, conformation-specific antibodies. Furthermore, we measured VK serum concentrations (using HPLC) in PXE-like and PXE samples to evaluate the VK status. In PXE-like patients, we noted an accumulation of uncarboxylated Gla proteins, MGP, and OC in plasma, serum, and in the dermis. Serum levels of VK were normal in these patients. In PXE patients, we found similar, although not identical results for the Gla proteins in the circulation and dermal tissue. However, the VK serum concentration in PXE patients was significantly decreased compared with controls. Our findings allow us to conclude that ectopic mineralization in the PXE-like syndrome and in PXE results from a deficient protein carboxylation of VK-dependent inhibitors of calcification. Although in PXE-like patients this is due to mutations in the GGCX gene, a deficiency of the carboxylation co-factor VK is at the basis of the decreased activity of calcification inhibitors in PXE.

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The Circulating Inactive Form of Matrix Gla Protein (ucMGP) as a Biomarker for Cardiovascular Calcification

Cited by 161 publications

References 76 publications

Calcium scores and matrix Gla protein levels: association with vitamin K status

Calcium scores and matrix Gla protein levels: association with vitamin K status

Circulating Nonphosphorylated Carboxylated Matrix Gla Protein Predicts Survival in ESRD

Low serum vitamin K in PXE results in defective carboxylation of mineralization inhibitors similar to the GGCX mutations in the PXE-like syndrome

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