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Results for “Matrix Gla Protein”

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PubMed1996

Identification of the cell type origin of odontoma-like cell masses in microphthalmic (mi/mi) mice by in situ hybridization.

Tooth abnormalities occur in microphthalmic (mi/mi) mice. The elongated odontogenic epithelium is interrupted by unresorbed bone at the basal end of the mi/mi incisor, with the epithelium gathered into cell clusters. These clusters develop to odontoma-like masses. To identify the origin of the cell types of these odontoma-like masses, the localization of osteonectin (Osn), osteocalcin (Osc), osteopontin (Osp), matrix Gla protein (MGP) and amelogenin (Am) mRNA in the process of tooth development in mi/mi and +/+ mice was investigated by means of in situ hybridization. Decalcified mandibles of neonatal, 5-, 10-, 14-day-old mice were examined. Osn and Osc mRNA, which localized in osteoblasts and odontoblasts, were also detected in the cells of odontoma-like masses in mi/mi mice. The cells expressing these mRNA were short, columnar and odontoblast-like. Am mRNA was detected in ameloblasts. In mi/mi mice, Am mRNA was also detected in ameloblastic cell clusters, which were formed by the tall columnar cells in the odontoma-like masses. No apparent Osp mRNA expression was detected in the masses. These results indicated that even in odontogenic abnormal cells resulting from physical obstruction in mi/mi mice, the genes that are involved in normal tooth development were still expressed.

Animals↗

PubMed2005

Cardiovascular calcification in patients with end-stage renal disease.

Vascular calcifications are very frequent extraosseous calcifications in patients with chronic renal disease. They occur in the intima and in the media. They are associated with decreased arterial elasticity and increased mortality. The risk factors are: advanced age, duration of dialysis treatment, diabetes, increased phosphate concentration, the dose of Ca-containing phosphate binders and inflammation. It is now well established that vascular smooth muscle cells actively take up phosphate to form bioapatite. This process is associated with a phenotypic transformation of vascular smooth muscle cells during which they express osteoblast markers. Lipids and inflammatory cytokines also increase bioapatite formation. Calcification inhibitors are matrix Gla protein and fetuin-A. Decreased serum fetuin-A concentration is associated with a higher mortality rate in dialysis patients. An important preventive measure for vascular calcification is the substitution of Ca-containing by non-Ca-containing phosphate binders.

Calcinosis↗

PubMed2005

Identification of persistently altered gene expression in the kidney after functional recovery from ischemic acute renal failure.

Recovery from ischemic acute renal failure (ARF) involves a well-described regenerative process; however, recovery from ARF also results in a predisposition to a progressive renal disease that is not well understood. This study sought to identify alterations in renal gene expression in postischemic, recovered animals that might play important roles in this progressive disorder. RNA isolated from sham-operated control rats or rats 35 days after recovery from bilateral ischemia-reperfusion (I/R) injury was compared using a cDNA microarray containing approximately 2,000 known rat genes. A reference hybridization strategy was utilized to define a 99.9% interval and to identify 16 genes that were persistently altered after recovery from I/R injury (12 were upregulated and 4 were downregulated). Real-time PCR verified the altered expression of six of eight genes that had been positively identified. Several genes that were identified had not previously been evaluated within the context of ARF. S100A4, a specific marker of fibroblasts, was identified in a population of interstitial cells that were present postischemic injury. S100A4-positive cells were also identified in tubular cells at earlier time points postischemia. Genes associated with calcification, including osteopontin and matrix Gla protein, were also enhanced postischemic injury. Several proinflammatory genes were identified, including complement C4, were enhanced in postischemic tissues. Conversely, renal kallikrein expression was specifically reduced in the postischemic kidney. In summary, genes with known inflammatory, remodeling, and vasoactive activities were identified in rat kidneys after recovery from ARF, some of which may play a role in altering long-term renal function after recovery from ARF.

Acute Kidney Injury↗

PubMed2004

Beneficial effects of vitamins D and K on the elastic properties of the vessel wall in postmenopausal women: a follow-up study.

Matrix-Gla Protein (MGP) is a strong inhibitor of vascular calcification, the expression of which is vitamin D dependent. MGP contains five gamma-carboxyglutamic acid (Gla)-residues which are formed in a vitamin K-dependent carboxylation step and which are essential for its function. Hence vascular vitamin K-deficiency will result in undercarboxylated, inactive MGP which is a potential risk factor for calcification. In the present study we describe the effects of vitamin K1 and D supplementation on vascular properties in postmenopausal women. In a randomized placebo-controlled intervention study, 181 postmenopausal women were given either a placebo or a supplement containing minerals and vitamin D (MD-group), or the same supplement with vitamin K1 (MDK-group). 150 participants completed the study and analysis was performed on 108 participants. At baseline and after three years, vessel wall characteristics, including compliance coefficient (CC), distensibility coefficient (DC), intima-media thickness (IMT) and the Young's Modulus (E) were measured to assess the effect of the supplements on the change of these parameters. The results showed that the elastic properties of the common carotid artery in the MDK-group remained unchanged over the three-year period, but decreased in the MD- and placebo-group. Comparing the MDK- and placebo-group, there were significant differences in decrease of DC (8.8%; p<0.05), CC (8.6%; p<0.05), and in increase of PP (6.3%; p<0.05) and E (13.2%, p<0.01). There were no significant differences between the MD-group and placebo. No significant differences were observed in the change of IMT between the three groups. It is concluded that a supplement containing vitamins K1 and D has a beneficial effect on the elastic properties of the arterial vessel wall.

Biomechanical Phenomena↗

PubMed2001

Bisphosphonates alendronate and ibandronate inhibit artery calcification at doses comparable to those that inhibit bone resorption.

The present experiments were carried out to test the hypothesis that artery calcification is linked to bone resorption by determining whether the selective inhibition of bone resorption with the bisphosphonates alendronate and ibandronate will inhibit artery calcification. Artery calcification was first induced by treatment of 42-day-old male rats with warfarin, a procedure that inhibits the gamma-carboxylation of matrix Gla protein and has been shown to cause extensive calcification of the artery media within 2 weeks. These experiments revealed that ibandronate (0.05 mg. kg(-1). d(-1)) and alendronate (0.1 mg x kg(-1) x d(-1)) completely inhibited calcification of all arteries and heart valves examined after 2 and 4 weeks of warfarin treatment. A 10-fold lower dose of alendronate reduced artery calcification by 50% (P<0.005). These bisphosphonate doses are comparable to those that inhibit bone resorption in rats of this age. More rapid artery calcification was induced by treatment with warfarin together with high doses of vitamin D, a procedure that causes extensive artery calcification by 84 hours. Alendronate and ibandronate again completely inhibited calcification of all arteries and heart valves examined. The subcutaneous doses of alendronate and ibandronate necessary to inhibit artery calcification are comparable to the daily subcutaneous doses of these drugs that have previously been shown to inhibit bone resorption in rats of the same age, with 50% inhibition of artery calcification at 20 microg alendronate x kg(-1) x d(-1) and at 1 microg ibandronate x kg(-1) x d(-1) x Bisphosphonate treatment did not affect serum calcium and phosphate, and so the inhibition of artery calcification cannot be due to a simple lowering of the serum calcium phosphate ion product. We conclude that bisphosphonates inhibit the calcification of arteries and heart valves at doses comparable to the doses that inhibit bone resorption. These results support the hypothesis that artery calcification is linked to bone resorption. The mechanism of this linkage remains to be established, however, and an alternative explanation for the present results is also considered.

Alendronate↗

PubMed2001

Osteoprotegerin inhibits artery calcification induced by warfarin and by vitamin D.

The present experiments were carried out to test the hypothesis that arterial calcification is linked to bone resorption by determining whether the selective inhibition of bone resorption with osteoprotegerin will inhibit arterial calcification. In the first test, arterial calcification was induced by treating 22-day-old male rats with warfarin, a procedure that inhibits the gamma-carboxylation of matrix Gla protein and causes extensive calcification of the arterial media. Compared with rats treated for 1 week with warfarin alone, rats treated with warfarin plus osteoprotegerin at a dose of 1 mg/kg per day had dramatically reduced alizarin red staining for calcification in the aorta and in the carotid, hepatic, mesenteric, renal, and femoral arteries, and they had 90% lower levels of calcium and phosphate in the abdominal aorta (P<0.001) and in tracheal ring cartilage (P<0.01). More rapid arterial calcification was induced by treating 49-day-old male rats with toxic doses of vitamin D. Treatment for 96 hours with vitamin D caused widespread alizarin red staining for calcification in the aorta and the femoral, mesenteric, hepatic, renal, and carotid arteries, and osteoprotegerin completely prevented calcification in each of these arteries and reduced the levels of calcium and phosphate in the abdominal aorta to control levels (P<0.001). Treatment with vitamin D also caused extensive calcification in the lungs, trachea, kidneys, stomach, and small intestine, and treatment with osteoprotegerin reduced or prevented calcification in each of these sites. Measurement of serum levels of cross-linked N-teleopeptides showed that osteoprotegerin dramatically reduced bone resorption activity in each of these experiments (P<0.001). Therefore, we conclude that doses of osteoprotegerin that inhibit bone resorption are able to potently inhibit the calcification of arteries that is induced by warfarin treatment and by vitamin D treatment. These results support the hypothesis that arterial calcification is linked to bone resorption.

Animals↗

PubMed2006

Vitamin K-containing dietary supplements: comparison of synthetic vitamin K1 and natto-derived menaquinone-7.

Vitamin K is a cofactor in the production of blood coagulation factors (in the liver), osteocalcin (in bone), and matrix Gla protein (cartilage and vessel wall). Accumulating evidence suggests that for optimal bone and vascular health, relatively high intakes of vitamin K are required. The synthetic short-chain vitamin K(1) is commonly used in food supplements, but recently the natural long-chain menaquinone-7 (MK-7) has also become available as an over-the-counter (OTC) supplement. The purpose of this paper was to compare in healthy volunteers the absorption and efficacy of K(1) and MK-7. Serum vitamin K species were used as a marker for absorption and osteocalcin carboxylation as a marker for activity. Both K(1) and MK-7 were absorbed well, with peak serum concentrations at 4 hours after intake. A major difference between the 2 vitamin K species is the very long half-life time of MK-7, resulting in much more stable serum levels, and accumulation of MK-7 to higher levels (7- to 8-fold) during prolonged intake. MK-7 induced more complete carboxylation of osteocalcin, and hematologists should be aware that preparations supplying 50 mug/d or more of MK-7 may interfere with oral anticoagulant treatment in a clinically relevant way.

Absorption↗

PubMed2001

Tracheobronchial stenosis in Keutel syndrome.

In 1971 Keutel et al. described a new syndrome in two siblings presenting with peripheral pulmonary stenoses, brachytelephalangism, neural hearing loss and abnormal cartilage calcification. Recent investigations provided evidence that mutations in the gene encoding the human matrix GLA protein cause Keutel syndrome. With these new insights in the disease the symptomatology of Keutel syndrome was reassessed. The follow-up of the two siblings was studied by clinical and post mortem examination. As a new feature of Keutel syndrome tracheobronchial stenosis and concentric calcification of pulmonary, coronary, hepatic, renal, meningeal and cerebral arteries were described. Complementary to the results in molecular genetics the symptomatology of Keutel syndrome could be revised by clinical and post mortem examination.

Abnormalities, Multiple↗

PubMed1999

Discovery and characterization of endometrial epithelial messenger ribonucleic acids using the ovine uterine gland knockout model.

Prolonged exposure of the developing neonatal ovine uterus to a progestin from birth prevents uterine gland development and creates an adult endometrial phenotype characterized by the absence of glandular epithelium, the uterine gland knockout (UGKO) phenotype. This study used endometrium from normal and UGKO sheep to identify messenger RNAs (mRNAs) expressed differentially in the endometrial epithelium using the molecular techniques of mRNA differential display PCR (DD-PCR) and suppression subtractive complementary DNA (cDNA) hybridization (SSH). Sequence analyses of DD- and SSH-identified and cloned cDNAs indicated similarity of some to known mRNAs, including beta-lactoglobulin, alkaline phosphatase, type B and D endogenous sheep retroviruses, gp330/megalin, matrix Gla protein, and others. Other cDNAs were not similar to any known sequences and are considered novel, although some of these match human expressed sequence tags. In situ hybridization analyses of uteri from cyclic and pregnant ewes indicated that all DD-PCR- and SSH-identified mRNAs were expressed in either the endometrial lumenal and/or glandular epithelium, although some were also expressed in other uterine cell types. Northern and in situ hybridization analyses revealed that patterns of mRNA expression for most clones were affected by the day of the estrous cycle and pregnancy in a manner consistent with regulation by progesterone. Studies demonstrate the utility of the ovine UGKO model as a tool with which to identify known and novel uterine epithelial-specific genes. Cloned cDNAs identified here are expressed sequence tags useful for comparative and physical genetic mapping and may be used to reveal new factors and pathways regulating endometrial function.

Animals↗

PubMed2001

Signal-selectivity of parathyroid hormone (PTH)/PTH-related peptide receptor-mediated regulation of differentiation in conditionally immortalized growth-plate chondrocytes.

Type-1 PTH/PTH-related peptide receptors (PTH1Rs), which activate both adenylyl cyclase and phospholipase C (PLC), control endochondral bone development by regulating chondrocyte differentiation. To directly analyze PTH1R function in such cells, we isolated conditionally transformed clonal chondrocytic cell lines from tibial growth plates of neonatal mice heterozygous for PTH1R gene ablation. Among 104 cell lines isolated, messenger RNAs for PTH1R, collagen II, and collagen X were detected in 28%, 90%, and 29%, respectively. These cell lines were morphologically diverse. Some appeared large, rounded, and enveloped by abundant extracellular matrix; whereas others were smaller, flattened, and elongated. Two PTH1R-expressing clones showed similar PTH1R binding and cAMP responsiveness to PTH and PTH-related peptide but disparate morphologic features, characteristic of hypertrophic (hC1--5) or nonhypertrophic (nhC2--27) chondrocytes, respectively. hC1--5 cells expressed messenger RNAs for collagen II and X, alkaline phosphatase (ALP), and matrix GLA protein, whereas nhC2--27 cells expressed collagen II and Indian hedgehog but not collagen X or ALP. In hC1--5 cells, PTH and cAMP analog, but not phorbol ester, inhibited both ALP and mineralization. PTH1R-null hC1--5 subclones were isolated by in vitro selection and then reconstituted by stable transfection with wild-type PTH1Rs or mutant (DSEL) PTH1Rs defective in PLC activation. ALP and mineralization were inhibited similarly via both forms of the receptor. These results indicate that PLC activation is not required for PTH1R regulation of mineralization or ALP in hypertrophic chondrocytes and are consistent with a major role for cAMP in regulating differentiation of hypertrophic chondrocytes.

Animals↗

PubMed2001

The expression of the urokinase plasminogen activator system in metastatic murine osteosarcoma: an in vivo mouse model.

The role of urokinase plasminogen activator (uPA) in osteosarcoma is poorly understood. We examined the importance of uPA, its receptor, uPAR, and its inhibitor, PAI-1, in our in vivo model of metastatic osteosarcoma. Rodent osteosarcoma cells (UMR 106-01) were inoculated into the tibia of athymic mice. Animals were sacrificed and autopsied at 4 days to 5 weeks after inoculation. Tibiae and lungs were excised, fixed, and examined histologically and by in situ hybridization. Osteosarcoma development was associated with tibial swelling and lameness, and radiographic changes included osteolysis and new bone formation. Lung metastases developed spontaneously. In the tibial tumors, uPAR mRNA was expressed early (4 days), whereas uPA and PAI-1 mRNA increased as the tumor invaded the surrounding tissue (3 weeks). There was also an increase in the mRNA expression of the osteoblast-related genes, alpha1(I) procollagen and osteopontin, but not matrix Gla protein. Lung metastases also expressed mRNA for the uPA system and the bone-related proteins. We have produced a model of metastatic osteosarcoma, which typifies the characteristics of the human tumor. Our results suggest that the uPA system plays a role in the local aggressiveness and metastasis of osteosarcoma and, in particular, indicates a possible therapeutic role for uPAR antagonists in the treatment of osteosarcoma.

Animals↗

PubMed2002

Construction of human corneal endothelial cDNA library and identification of novel active genes.

PURPOSE: To describe genes expressed in human corneal endothelial cells and identify novel genes. METHODS: Sixteen human donor corneas that had no history of corneal disease, infection, or intraocular surgery were used within 7 days of death. Total RNA was extracted from corneal endothelial cells with attached Descemet membranes. A 3'-directed cDNA library was constructed from mRNA by using a pUC19-based primer. These sequences were compared with each other to determine their frequency and were searched against GenBank for identification. To identify novel specific and abundant transcript genes in corneal endothelial cells, the novel genes were compared with an expressed sequence tag database, the expected sequence extended, and 5' rapid amplification of cDNA ends-polymerase chain reaction cloning performed. RESULTS: The human corneal endothelial cDNA library showed that the most abundant transcript was prostaglandin D2 synthase. The remaining transcript genes that were present in abundance consisted of lactate dehydrogenase-A, gene signature (GS) 3582, which is a novel gene without a known function, and matrix Gla protein. The full-length sequence of GS3582 showed similarity to genes obtained in ovary and TESTIS. CONCLUSIONS: A human corneal endothelial cDNA library was constructed. An expression profile of corneal endothelium provides probes to monitor physiologic and pathologic conditions of this tissue in terms of gene expression.

Aged↗

PubMed2002

[Close relationship between bone and vasculature].

Cardiovascular disease and osteoporosis are major causes of morbidity and mortality in elderly and postmenopausal women. Vascular calcification is a common feature of atherosclerotic plaques and is regulated in a way similar to bone mineralization. Several studies revealed that atherosclerotic calcification is associated with bone loss in women. In this review, we focus on the new developments during the past year in relationship between bone and vasculature. Regulatory factors include matrix GLA protein, osteoprotegerin, klotho gene, bisphosphonates and statins.

English Abstract↗

PubMed2006

Genome-wide expression profile of human trabecular meshwork cultured cells, nonglaucomatous and primary open angle glaucoma tissue.

PURPOSE: To contrast genome-wide gene expression profiles of cultured human trabecular meshwork (HTM) cells to that of control and primary open angle glaucoma (POAG) HTM tissues. METHODS: Cultured HTM cells, HTM tissue dissected from control donors, and HTM tissue from POAG donors receiving medication for glaucoma were fixed in RNA latertrade mark. Total RNA extracted from these samples was linearly amplified with the Ovation Biotin RNA Amplification and Labeling System and individually hybridized to Affymetrix Human Genome U133 Plus 2.0 high density microarrays. Data analysis was performed using GeneSpring Software 7.0. Selected genes showing significant differential expression were validated by quantitative real-time PCR in nonamplified RNA. RESULTS: Cultured HTM cells retained the expression of some genes characteristic of HTM tissue, including chitinase 3-like 1 and matrix Gla protein, but demonstrated downregulation of physiologically important genes such as myocilin. POAG HTM tissue showed relatively small changes compared to that of control donors. These changes included the statistically significant upregulation of several genes associated with inflammation and acute-phase response, including selectin-E (ELAM-I), as well as the downregulation of the antioxidants paraoxonase 3 and ceruloplasmin. CONCLUSIONS: Downregulation in cultured HTM cells of genes potentially relevant for outflow pathway function highlights the importance of developing new conditions for the culture of TM cells capable of preserving the characteristics of TM cells in vivo. Comparative analysis between control and POAG tissues suggests that the upregulation of inflammation-associated genes might be involved in the progression of glaucoma.

Case-Control Studies↗

PubMed2004

Dietary intake of menaquinone is associated with a reduced risk of coronary heart disease: the Rotterdam Study.

Vitamin K-dependent proteins, including matrix Gla-protein, have been shown to inhibit vascular calcification. Activation of these proteins via carboxylation depends on the availability of vitamin K. We examined whether dietary intake of phylloquinone (vitamin K-1) and menaquinone (vitamin K-2) were related to aortic calcification and coronary heart disease (CHD) in the population-based Rotterdam Study. The analysis included 4807 subjects with dietary data and no history of myocardial infarction at baseline (1990-1993) who were followed until January 1, 2000. The risk of incident CHD, all-cause mortality, and aortic atherosclerosis was studied in tertiles of energy-adjusted vitamin K intake after adjustment for age, gender, BMI, smoking, diabetes, education, and dietary factors. The relative risk (RR) of CHD mortality was reduced in the mid and upper tertiles of dietary menaquinone compared to the lower tertile [RR = 0.73 (95% CI: 0.45, 1.17) and 0.43 (0.24, 0.77), respectively]. Intake of menaquinone was also inversely related to all-cause mortality [RR = 0.91 (0.75, 1.09) and 0.74 (0.59, 0.92), respectively] and severe aortic calcification [odds ratio of 0.71 (0.50, 1.00) and 0.48 (0.32, 0.71), respectively]. Phylloquinone intake was not related to any of the outcomes. These findings suggest that an adequate intake of menaquinone could be important for CHD prevention.

Aortic Diseases↗

PubMed2002

The induction of c-fos mRNA expression by mechanical stress in human periodontal ligament cells.

The periodontal ligament is subjected to mechanical loading during occlusion and mastication. Although internuclear transcription factors are associated with the regulatory pathway that converts these extracellular mechanical stimuli into a cellular response, there are no reports on these in human periodontal ligament fibroblasts. In this study, the amounts of c-fos mRNA in human periodontal ligament fibroblasts were investigated shortly after subjecting them to a cyclic tension force in vitro. The mRNA of alkaline phosphatase and the matrix proteins type I collagen, type III collagen, matrix Gla-protein, osteonectin, osteopontin, and osteocalcin were also examined. A significant, rapid, transient increase in c-fos mRNA was detected, which peaked 30 min after the application of mechanical force. However, there was no significant change in the mRNA for alkaline phosphatase or the matrix proteins. These results provide evidence that periodontal ligament fibroblasts and c-fos may play a critical part in the response of periodontal tissue to mechanical stimulation.

1-Carboxyglutamic Acid↗

PubMed1996

Effect of Ca2+ on the structure of vitamin K-dependent coagulation factors.

Coagulation factors VII, IX, X, and protein C contain an N-terminal module with 9-12 gamma-carboxyglutamic acid (Gla) residues. It is followed by two modules that are homologous to the epidermal growth factor (EGF) and a C-terminal serine protease module. Upon calcium binding to the Gla module the side chains of three hydrophobic residues are exposed in a manner indicating that they interact with biological membranes. The calcium-binding site in the first EGF-like module appears to be required for proper orientation of the Gla and EGF-like modules relative to each other. A single calcium-binding site is also present in the serine protease module. The properties of these calcium-binding sites are briefly reviewed.

Amino Acid Sequence↗

PubMed2001

Role of vitamin K and vitamin K-dependent proteins in vascular calcification.

OBJECTIVES: To provide a rational basis for recommended daily allowances (RDA) of dietary phylloquinone (vitamin K1) and menaquinone (vitamin K2) intake that adequately supply extrahepatic (notably vascular) tissue requirements. BACKGROUND: Vitamin K has a key function in the synthesis of at least two proteins involved in calcium and bone metabolism, namely osteocalcin and matrix Gla-protein (MGP). MGP was shown to be a strong inhibitor of vascular calcification. Present RDA values for vitamin K are based on the hepatic phylloquinone requirement for coagulation factor synthesis. Accumulating data suggest that extrahepatic tissues such as bone and vessel wall require higher dietary intakes and have a preference for menaquinone rather than for phylloquinone. METHODS: Tissue-specific vitamin K consumption under controlled intake was determined in warfarin-treated rats using the vitamin K-quinone/epoxide ratio as a measure for vitamin K consumption. Immunohistochemical analysis of human vascular material was performed using a monoclonal antibody against MGP. The same antibody was used for quantification of MGP levels in serum. RESULTS: At least some extrahepatic tissues including the arterial vessel wall have a high preference for accumulating and using menaquinone rather than phylloquinone. Both intima and media sclerosis are associated with high tissue concentrations of MGP, with the most prominent accumulation at the interface between vascular tissue and calcified material. This was consistent with increased concentrations of circulating MGP in subjects with atherosclerosis and diabetes mellitus. CONCLUSIONS: This is the first report demonstrating the association between MGP and vascular calcification. The hypothesis is put forward that undercarboxylation of MGP is a risk factor for vascular calcification and that the present RDA values are too low to ensure full carboxylation of MGP.

Arteriosclerosis↗