Role Of Matrix Gla Protein Research Articles

Molecular mechanisms mediating vascular calcification: Role of matrix Gla protein (Review Article)

Patients with chronic kidney disease (CKD) have a higher incidence of vascular calcification and a greatly increased risk of cardiovascular death. The mechanisms involved in the accelerated vascular calcification observed in CKD have recently become clearer, leading to the hypothesis that a lack of natural inhibitors of calcification may trigger calcium deposition. One of these inhibitory factors, matrix Gla protein (MGP), is the focus of the present review. MGP, originally isolated from bone, is a vitamin K-dependent protein that is also highly expressed by vascular smooth muscle cells. MGP has been confirmed as a calcification-inhibitor in numerous studies; however, its mechanism of action is not completely understood. It potentially acts in several ways to regulate calcium deposition including: (i) binding calcium ions and crystals; (ii) antagonizing bone morphogenetic protein and altering cell differentiation; (iii) binding to extracellular matrix components; and (iv) regulating apoptosis. Its expression is regulated by several factors including retinoic acid, vitamin D and extracellular calcium ions, and a reduced form of vitamin K (KH2) is important in maintaining MGP in an active form. Therefore, strategies aimed at increasing its expression and activity may be beneficial in tipping the balance in favour of inhibition of calcification in CKD.

Matrix Gla protein (MGP) and bone morphogenetic protein-2 in aortic calcified lesions of aging rats

The vitamin K-dependent protein, matrix Gla protein (MGP) is a binding protein for bone morphogenetic protein-2 (BMP-2). Here we present additional evidence that the Ca2+-induced conformer of the vitamin K-dependent Gla region in MGP is involved in BMP-2 binding. Recombinant BMP-2 binds to the Gla-containing region of MGP in the presence of Ca2+. Immunohistochemistry showed that calcified lesions in the aortic wall of aging rats contained elevated concentrations of MGP that was poorly gamma-carboxylated and did not bind BMP-2. In contrast, we were able to identify glandular structures in the mucosa of the rat nasal septum that gave bright fluorescent signals with both antigens; confocal microscopy confirmed their colocalization. These results demonstrate that the BMP-2/MGP complex exists in vivo, consistent with a role for MGP as a BMP-2 inhibitor. Age-related arterial calcification may be a consequence of under-gamma-carboxylation of MGP, allowing unopposed BMP-2 activity.

Novel Insights into Uremic Vascular Calcification: Role of Matrix Gla Protein and Alpha-2-Heremans Schmid Glycoprotein/Fetuin

Cardiovascular mortality is markedly increased in the dialysis population when compared to non-uremic subjects. Vascular and valvular calcifications are most frequently found in dialysis patients at risk and are independent predictors of cardiovascular death in this population. Traditionally, the presence of hyperphosphatemia and an increased calcium × phosphate product was considered a major pathomechanistic condition leading to excessive vascular and soft-tissue calcifications in uremic subjects. Recent studies in knockout mice, however, revealed that deficiencies in calcium-regulatory proteins may also directly contribute to the development of extraosseus calcifications. α₂-Heremans Schmid glycoprotein and matrix Gla protein are important inhibitors of calcification in vivo and there is novel evidence available that a deficiency in such proteins is involved in the pathogenesis of cardiovascular calcifications in dialysis patients.

Down-regulation of matrix Gla protein messenger RNA in human colorectal adenocarcinomas

Matrix Gla protein (MGP) is a vitamin K-dependent extracellular matrix protein commonly found in a variety of tissues. In this study, we describe the potential use of MGP gene expression as the tumor marker of colorectal cancer. A decrease in expression of the MGP gene was also discovered in colorectal cancer using differential screening of cDNA libraries. The MGP expression in 80 human colorectal adenocarcinomas was quantified by a Northern blot analysis to better define the expression pattern of MGP in colorectal cancer. The expression of MGP mRNA was reduced in 63 of 80 (79%) colorectal adenocarcinomas ( P<0.001) as compared to the mRNA in adjacent normal tissue, implying that a decrease in MGP expression is associated with colorectal cancer development. The proportion of tumors with downregulated expression of MGP was lower in Duke's A/B than Duke's C/D (34 of 47 versus 26 of 33, respectively) tumors and was lower in moderate differentiation than poor differentiation (44 of 64 versus 16 of 16, respectively). However, χ 2 analysis does not reveal any correlation between a loss of MGP expression and tumor progression or differentiation state. In conclusion, the downregulation of MGP mRNA generally occurs in colorectal adenocarcinomas. Although the role of MGP in cancer development is unknown, the reduced expression of MGP may be used to distinguish the normal colorectal cells from malignant cells.

Role of vitamin K and Gla proteins in the pathophysiology of osteoporosis and vascular calcification.

Among the proteins known or suspected to be involved in bone and vascular biology are several members of the vitamin K-dependent or Gla protein family. This review focuses on the role of two of these: osteocalcin and matrix Gla protein. Osteocalcin metabolism has been implicated in the pathogenesis of osteoporosis through an unknown mechanism that may be linked to suboptimal vitamin K status resulting in its undercarboxylation and presumed dysfunction. Recent studies that have investigated this hypothesis are discussed, as are recent promising clinical studies of vitamin K supplementation in osteoporosis. A recently delineated function of matrix Gla protein is as a powerful inhibitor of calcification of arteries and cartilage. In the period covered by this review there have been several landmark studies using cell systems, whole animals and genetic techniques that have consolidated and extended our knowledge of the role of matrix Gla protein in the prevention of ectopic calcification.

Expression of matrix Gla protein (MGP) in an in vitro model of vascular calcification

To investigate the role of matrix Gla protein (MGP), which can bind mineral ions through γ-carboxylated glutamic acid residues, in vascular calcification, we examined the expression of MGP in an in vitro calcification model by using bovine vascular smooth muscle cells (BVSMC). The expression of MGP mRNA was decreased during BVSMC calcification and its levels were inversely correlated with the quantities of BVSMC calcification. MGP mRNA expression was restored to the level of uncalcified control by inhibiting BVSMC calcification with bisphosphonates. These data suggest that the expression of MGP gene is modulated in the development of vascular calcification.