Matrix Gla Protein Accumulates at the Border of Regions of Calcification and Normal Tissue in the Media of the Arterial Vessel Wall

Spronk, Henri M. H.; Soute, Berry A.M.; Schurgers, Leon J.; Cleutjens, Jack P.M.; Thijssen, H. H. W.; Mey, Jo G. R. De; Vermeer, Cees

doi:10.1006/bbrc.2001.5996

Cited by 113 publications

(81 citation statements)

References 20 publications

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“…This result is similar to that obtained by Spronk et al [22] in human fetal bone, by using two monoclonal antibodies, against the N-and C-terminus of MGP. In contrast, Carlson et al [23] reported slight positive IHC staining for total MGP in widely scattered areas of calcified matrix in vertebrae of monkeys.…”

Section: Discussionsupporting

confidence: 91%

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Immunohistochemical localization and mRNA expression of matrix Gla protein and fetuin-A in bone biopsies of hemodialysis patients

et al. 2009

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Matrix Gla protein (MGP) and fetuin-A are inhibitors of arterial calcifications. In blood of rats, calcium-phosphate-fetuin-MGP complexes, produced in bone, have been identified. Indeed, an association between bone resorption, release of such complexes, and arterial calcifications has been reported. We have investigated the synthesis and localization of fetuin-A and MGP in bone of hemodialysis patients and the possible contribution of bone cells in arterial calcifications. Bone biopsies from 11 hemodialysis patients were used for histology, in situ hybridization of fetuin-A and MGP messenger RNA (mRNA), immunohistochemistry of fetuin-A, and total, carboxylated, and non-carboxylated MGP proteins. Patients showed various types of renal osteodystrophy, or normal bone. MGP was synthesized and expressed (total and carboxylated) by osteoblasts, osteocytes, and most osteoclasts, while fetuin-A by osteoblasts and osteocytes. Fetuin-A and carboxylated MGP proteins were positive in the calcified matrix, while total MGP was negative. Osteoid seams were negative to fetuin-A, lightly positive to carboxylated MGP, and occasionally positive to total MGP. Undercarboxylated MGP was mostly undetectable. In adult humans, fetuin-A is produced also by osteoblasts, and not only by hepatocytes, as previously believed. MGP, essentially carboxylated, is synthesized by osteoblasts and most osteoclasts. Increased bone turnover can be an important contributor to arterial calcifications.

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Section: Discussionsupporting

confidence: 91%

“…In human fetal bone, Spronk et al [22] reported a weak total MGP signal that was associated with the extracellular matrix at sites of non-calcified bone. Moreover, Carlson et al [23] found some areas of osteoid seams positive to total MGP.…”

Section: Discussionmentioning

confidence: 99%

Immunohistochemical localization and mRNA expression of matrix Gla protein and fetuin-A in bone biopsies of hemodialysis patients

et al. 2009

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“…24,25 Moreover, in aortas, mineralization induced by warfarin was observed limited to elastic fibers, in the absence of necrotic material, and therefore attributable to an active process. 22,26 Therefore, defects in MGP carboxylation seems to be associated with elastin mineralization. In a recent paper, dermal elastic fiber calcification has been extensively described in patients affected by coagulation disorders due to a genetic defect in vitamin K recycling with consequent deficient protein g-carboxylation.…”

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confidence: 99%

Matrix Gla protein is involved in elastic fiber calcification in the dermis of pseudoxanthoma elasticum patients

Gheduzzi

Boraldi

Annovi

et al. 2007

Laboratory Investigation

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Mature MGP (Matrix g-carboxyglutamic acid protein) is known to inhibit soft connective tissues calcification. We investigated its possible involvement in pseudoxanthoma elasticum (PXE), a genetic disorder whose clinical manifestations are due to mineralization of elastic fibers. PXE patients have lower serum concentration of total MGP compared to controls (Po0.001). Antibodies specific for the noncarboxylated (Glu-MGP) and for the g-carboxylated (Gla-MGP) forms of MGP were assayed on ultrathin sections of dermis from controls and PXE patients. Normal elastic fibers in controls and patients were slightly positive for both forms of MGP, whereas Gla-MGP was more abundant within control's than within patient's elastic fibers (Po0.001). In patients' calcified elastic fibers, Glu-MGP intensively colocalized with mineral precipitates, whereas Gla-MGP precisely localized at the mineralization front. Data suggest that MGP is present within elastic fibers and is associated with calcification of dermal elastic fibers in PXE. To investigate whether local cells produce MGP, dermal fibroblasts were cultured in vitro and MGP was assayed at mRNA and protein levels. In spite of very similar MGP mRNA expression, cells from PXE patients produced 30% less of Gla-MGP compared to controls. Data were confirmed by immunocytochemistry on ultrathin sections. Normal fibroblasts in vitro were positive for both forms of MGP. PXE fibroblasts were positive for Glu-MGP and only barely positive for Gla-MGP (Po0.001). In conclusion, MGP is involved in elastic fiber calcification in PXE. The lower ratio of Gla-MGP over Glu-MGP in pathological fibroblasts compared to controls suggests these cells may play an important role in the ectopic calcification in PXE.

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“…Each antibody recognized either BGP or MGP with no cross-reaction between proteins detected. All purified fish BGPs and MGPs tested were shown to be specifically recognized, thus validating the use of these antibodies for further studies.Matrix Gla Protein (MGP) and Bone Gla Protein (BGP, osteocalcin) belong to the family of vitamin K-dependent (VKD), c-carboxyglutamic acid (Gla)-containing proteins that have been unequivocally associated with bone formation and mineralization [1][2][3][4], and more recently, with vascular calcification [5][6][7][8][9][10].MGP is a 10-15 kDa-secreted protein, containing 4-5 residues (depending on the species) of the Ca 2+ binding Gla residue [11][12][13][14][15] while BGP is a small secreted protein with approximately 6 kDa molecular weight and includes three Gla residues. Although there is little information about the regulation of expression of these proteins in teleosts, BGP in teleost fish has been shown to be associated with bone-like mineralized tissues present in branchial arches, jaw, vertebra and scales [15,16] while MGP was only recently found to accumulate, mainly in the extracellular matrix of calcified cartilage [15].…”

mentioning

confidence: 99%

“…Matrix Gla Protein (MGP) and Bone Gla Protein (BGP, osteocalcin) belong to the family of vitamin K-dependent (VKD), c-carboxyglutamic acid (Gla)-containing proteins that have been unequivocally associated with bone formation and mineralization [1][2][3][4], and more recently, with vascular calcification [5][6][7][8][9][10].…”

mentioning

confidence: 99%

Characterization of Osteocalcin (BGP) and Matrix Gla Protein (MGP) Fish Specific Antibodies: Validation for Immunodetection Studies in Lower Vertebrates

Simes

Williamson

Schaff

et al. 2004

Calcified Tissue International

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Abstract. In fish species the basic mechanisms of bone development and bone remodeling are not fully understood. The classification of bone tissue in teleosts as cellular or acellular and the presence of transitional states between bone and cartilage and the finding of different types of cartilage in teleosts not previously recognized in higher vertebrates emphasizes the need for a study on the accumulation of the Gla-containing proteins MGP and BGP at the cellular level. In the present study, polyclonal antibodies developed against BGP and MGP from A. regius (a local marine teleost fish) and against MGP from G. galeus (a Pacific Ocean shark), were tested by Western blot for their specificity against BGP and MGP from several other species of teleost fish and shark. For this purpose we extracted and purified both proteins from various marine and freshwater teleosts, identified them by N-terminal amino acid sequence analysis and confirmed the presence of gamma-carboxylation in the proteins with the use of a stain specific for Gla residues. Each antibody recognized either BGP or MGP with no cross-reaction between proteins detected. All purified fish BGPs and MGPs tested were shown to be specifically recognized, thus validating the use of these antibodies for further studies.Matrix Gla Protein (MGP) and Bone Gla Protein (BGP, osteocalcin) belong to the family of vitamin K-dependent (VKD), c-carboxyglutamic acid (Gla)-containing proteins that have been unequivocally associated with bone formation and mineralization [1][2][3][4], and more recently, with vascular calcification [5][6][7][8][9][10].MGP is a 10-15 kDa-secreted protein, containing 4-5 residues (depending on the species) of the Ca 2+ binding Gla residue [11][12][13][14][15] while BGP is a small secreted protein with approximately 6 kDa molecular weight and includes three Gla residues. Although there is little information about the regulation of expression of these proteins in teleosts, BGP in teleost fish has been shown to be associated with bone-like mineralized tissues present in branchial arches, jaw, vertebra and scales [15,16] while MGP was only recently found to accumulate, mainly in the extracellular matrix of calcified cartilage [15]. In this previous work, the MGP gene was found to be predominantly expressed in chondrocytes from branchial arches, with no expression detected in the different bone-like mineralized tissues analyzed while BGP mRNA was mainly located in bony tissues associated with osteoblast-like cells, as expected [15]. As previously seen in mammals and Xenopus, MGP mRNA was also found to be present in teleost soft tissues, predominantly in heart and kidney [15], with the expression of MGP in heart tissue mainly associated with two specific cell types, smooth muscle and endothelial cells [15].We have recently developed specific polyclonal antibodies against BGP and MGP from the teleost fish A. regius [15] as well as against MGP purified from soupfin shark (Galeorhinus galeus) (our unpublished results). The purpose of the present work ...

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Matrix Gla Protein Accumulates at the Border of Regions of Calcification and Normal Tissue in the Media of the Arterial Vessel Wall

Cited by 113 publications

References 20 publications

Immunohistochemical localization and mRNA expression of matrix Gla protein and fetuin-A in bone biopsies of hemodialysis patients

Immunohistochemical localization and mRNA expression of matrix Gla protein and fetuin-A in bone biopsies of hemodialysis patients

Matrix Gla protein is involved in elastic fiber calcification in the dermis of pseudoxanthoma elasticum patients

Characterization of Osteocalcin (BGP) and Matrix Gla Protein (MGP) Fish Specific Antibodies: Validation for Immunodetection Studies in Lower Vertebrates

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