Characterisation and potential diagnostic value of circulating matrix Gla protein (MGP) species

Abstract

Matrix γ-carboxyglutamate (Gla) protein (MGP) is an important local inhibitor of vascular calcification, which can undergo two post-translational modifications: vitamin K-dependent γ-glutamate carboxylation and serine phosphorylation. While carboxylation is thought to have effects upon binding of calcium-ions, phosphorylation is supposed to affect the cellular release of MGP. Since both modifications can be exerted incompletely, various MGP species can be detected in the circulation. MGP levels were measured with two commercially available competitive and two novel sandwich assays in healthy controls, in patients with rheumatic disease, aortic valve disease, and end-stage renal disease, as well as in volunteers after vitamin K supplementation (VKS) and treatment with vitamin K antagonists (VKA). Major differences were found between the MGP assays, including significantly different behaviour with regard to vascular disease and the response to VKA and VKS. The dual-antibody assay measuring non-phosphorylated, non-carboxylated MGP (dp-ucMGP) was particularly sensitive for these changes and would be suited to assess the vascular vitamin K status. We conclude that the different assays for particular circulating MGP species allows the assessment of various aspects of the MGP system.

RNA Sequencing Identifies Novel Translational Biomarkers of Kidney Fibrosis

“…For example, MGP is involved in vascular fibrosis and calcification, where measurements of its circulatory forms are being tested as markers for this occurrence even in the context of ESRD. 17 Considering the impaired lipid metabolism in CKD, particularly as it relates to triglycerides and HDL, plasma PLTP was investigated as marker of ESRD, with no detectable changes. 21 Some of the transmembrane proteins that we have identified, like CDH11 and MRC1, have been previously shown to be involved in fibrosis.…”

“…While some of our candidates have already been linked to fibrosis in other organs, with Cdh11 found in lungs 15 and arthritis 16 and Mgp in vascular fibrosis, 17 we decided to test the kidney specificity for our panel in samples from a mouse model and human patients with liver fibrosis. Using Picrosirius red staining in Figure 5A, a-naphthylisothiocyanate (ANIT) exposure (an established model to induce liver fibrosis in mice 18 ) significantly increased peribiliary fibrosis when compared with mice fed a control diet.…”

Outcome of a public consultation on the Draft Scientific Opinion of the EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA) on Dietary Reference Values for vitamin K

“…It was pointed out that, on average, 20-30% of the circulating osteocalcin and dp-ucMGP occurs in the uncarboxylated (inactive) form (Cranenburg et al, 2010;Theuwissen et al, 2014), thus that, in the tissues where they have been produced, there is insufficient vitamin K to convert all of these precursor proteins into active proteins.…”

New Perspectives for the Nutritional Value of Vitamin K in Human Health

“…MGP contains 4-5 Gla residues and is synthetized by chondrocytes, vascular smooth muscle cells (VSMCs), endothelial cells, and fibroblasts [51]. It is presently considered one of the most powerful vascular calcification inhibitor known to date, and it is undercarboxylated form has been proposed as a biomarker for cardiovascular calcification and for vitamin K status [51,[59][60][61]. Knockout mice for MGP die within 8 weeks of birth due to massive vascular mineralization of the main arteries, a phenotype similar to that obtain with warfarin treatments [62].…”