Vitamin K-Dependent Matrix Gla Protein as Multifaceted Protector of Vascular and Tissue Integrity

Abstract

Supplemental Digital Content is available in the text.

Figure 1.

Full activation of MGP (matrix Gla protein) requires 2 posttranslational modifications, that is, vitamin K–dependent carboxylation of glutamate at positions 2, 37, 41, 48, and 52 and serine phosphorylation at positions 3, 6, and 9 by a Golgi-casein kinase. MGP therefore occurs in 4 conformations: dp-ucMGP (desphospho-uncarboxylated MGP), dp-cMGP (desphospho-carboxylated MGP), p-ucMGP (phosphorylated-uncarboxylated MGP), and p-cMGP (phosphorylated-carboxylated MGP). Adapted from Hackeng et al with permission. Copyright ©2008, John Wiley and Sons.

Figure 2.

Synthesis, activation, secretion, and downstream actions of MGP (matrix Gla protein). Endothelial and vascular smooth muscle cells express MGP. Step 1: After translation in the endoplasmatic reticulum (ER), vitamin K activates MGP by stimulating γ-carboxylation. Step 2: dp-cMGP (desphospho-carboxylated MGP) can sequester intracellular calcium, thereby providing protection against injury caused by calcium deposition. Step 3: A Golgi-associated casein kinase phosphorylates the serine residues of dp-cMGP to p-cMGP (phosphorylated-carboxylated MGP), thereby facilitating secretion. Step 4: p-cMGP is secreted into the extracellular matrix or the circulation to inhibit soft tissue calcification, VSMC (vascular smooth muscle cell) trans-differentiation into OPC (osteochondrogenic progenitor cells) and signaling via the BMP (bone morphogenetic protein) pathway. Step 5: Inactive dp-ucMGP (desphospho-uncarboxylated MGP), a biomarker reflecting poor vitamin K status, escapes from cells into the blood stream but does not inhibit calcification. Copyright © 2018, Wei et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Figure 3.

Dependency of circulating dp-ucMGP (desphospho-uncarboxylated matrix Gla protein) on age and stage of chronic kidney disease in 1166 participants enrolled in the Flemish Study on Environment, Genes and Health Outcomes (FLEMENGHO). A, The number of participants contributing to the plotted value is given alongside the plotted value. B, Box plots represent the median, interquartile range (IQR) and fifth to 95th percentile interval of the dp-ucMGP level in all participants and in participants with stage 1 (n=543), 2 (n=563), or stage 3 (n=60) of chronic kidney disease according to the National Kidney Foundation (KDOQI) guideline. P values indicate the significance of the associations. Copyright © 2016, Wei et al. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).