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PubMed1999

Medial localization of mineralization-regulating proteins in association with Mönckeberg's sclerosis: evidence for smooth muscle cell-mediated vascular calcification.

BACKGROUND: Calcification of the media of peripheral arteries is referred to as Mönckeberg's sclerosis (MS) and occurs commonly in aged and diabetic individuals. Its pathogenesis is unknown, but its presence predicts risk of cardiovascular events and leg amputation in diabetic patients. Several studies have documented expression of bone-associated genes in association with intimal atherosclerotic calcification, leading to the suggestion that vascular calcification may be a regulated process with similarities to developmental osteogenesis. Therefore, we examined gene expression in vessels with MS to determine whether there was evidence for a regulated calcification process in the vessel media. METHODS AND RESULTS: In situ hybridization, immunohistochemistry, and semiquantitative reverse-transcription polymerase chain reaction were used to examine the expression of mineralization-regulating proteins in human peripheral arteries with and without MS. MS occurred in direct apposition to medial vascular smooth muscle cells (VSMCs) in the absence of macrophages or lipid. These VSMCs expressed the smooth muscle-specific gene SM22alpha and high levels of matrix Gla protein but little osteopontin mRNA. Compared with normal vessels, vessels with MS globally expressed lower levels of matrix Gla protein and osteonectin, whereas alkaline phosphatase, bone sialoprotein, bone Gla protein, and collagen II, all indicators of osteogenesis/chondrogenesis, were upregulated. Furthermore, VSMCs derived from MS lesions exhibited osteoblastic properties and mineralized in vitro. CONCLUSIONS: These data indicate that medial calcification in MS lesions is an active process potentially orchestrated by phenotypically modified VSMCs.

Adult↗
PubMed1998

Chronic metabolic acidosis reversibly inhibits extracellular matrix gene expression in mouse osteoblasts.

Chronic metabolic acidosis induces net calcium efflux from bone mineral through an increase in osteoclastic resorption and a decrease in osteoblastic matrix deposition and mineralization. To determine the effects of chronic metabolic acidosis on the expression of genes necessary for mineralization, we grew primary bone cells, which are principally osteoblasts, to confluence in neutral pH (7.5) medium and then switched the cells either to a neutral pH or to an acidic pH (7.1) differentiation medium. Cells were harvested for RNA at 4- to 7-day intervals for up to 44 days. By 36 days, there was extensive bone nodule formation and mineralization in cells cultured in neutral medium; however, there was a substantial decrease in nodule formation and mineralization in cells cultured in acidic medium. There was a marked increase in matrix Gla protein RNA and an increase in osteopontin RNA in neutral cultures; however, acidic medium almost completely prevented any increase. In contrast, RNA levels for osteonectin and transforming growth factor-beta1 were not altered by chronic acidosis. Additional cells were incubated in acid differentiation medium for 1, 2, or 3 wk and then transferred to neutral medium; in each case, there was recovery of matrix Gla protein RNA and osteopontin RNA expression. Still other cells were incubated in neutral differentiation medium for 1, 2, or 3 wk and then transferred to acid medium; in each case there was inhibition of matrix Gla protein RNA and osteopontin RNA expression. Thus metabolic acidosis appears to specifically inhibit RNA accumulation of certain genes whose products may be essential for formation of mature bone matrix.

Acidosis↗
PubMed1994

High expression of genes for calcification-regulating proteins in human atherosclerotic plaques.

Calcification is common in atheromatous plaques and may contribute to plaque rupture and subsequent thrombosis. However, little is known about the mechanisms which regulate the calcification process. Using in situ hybridization and immunohistochemistry we show that two bone-associated proteins, osteopontin (OP) and matrix Gla protein (MGP), are highly expressed in human atheromatous plaques. High levels of OP mRNA and protein were found in association with necrotic lipid cores and areas of calcification. The predominant cell type in these areas was the macrophage-derived foam cell, although some smooth muscle cells could also be identified. MGP was expressed uniformly by smooth muscle cells in the normal media and at high levels in parts of the atheromatous intima. Highest levels of this matrix-associated protein were found in lipid-rich areas of the plaque. The pattern of expression of these two genes contrasted markedly with that of calponin and SM22 alpha, genes expressed predominantly by differentiated smooth muscle cells and whose expression was generally confined to the media of the vessel. The postulated function of OP and MGP as regulators of calcification in bone and the high levels and colocalization of both in atheromatous plaques suggest they have an important role in plaque pathogenesis and stability.

Arteriosclerosis↗
PubMed2001

Differential expression of bone matrix regulatory proteins in human atherosclerotic plaques.

In the present study, we examined the expression of regulators of bone formation and osteoclastogenesis in human atherosclerosis because accumulating evidence suggests that atherosclerotic calcification shares features with bone calcification. The most striking finding of this study was the constitutive immunoreactivity of matrix Gla protein, osteocalcin, and bone sialoprotein in nondiseased aortas and the absence of bone morphogenetic protein (BMP)-2, BMP-4, osteopontin, and osteonectin in nondiseased aortas and early atherosclerotic lesions. When atherosclerotic plaques demonstrated calcification or bone formation, BMP-2, BMP-4, osteopontin, and osteonectin were upregulated. Interestingly, this upregulation was associated with a sustained immunoreactivity of matrix Gla protein, osteocalcin, and bone sialoprotein. The 2 modulators of osteoclastogenesis (osteoprotegerin [OPG] and its ligand, OPGL) were present in the nondiseased vessel wall and in early atherosclerotic lesions. In advanced calcified lesions, OPG was present in bone structures, whereas OPGL was only present in the extracellular matrix surrounding calcium deposits. The observed expression patterns suggest a tight regulation of the expression of bone matrix regulatory proteins during human atherogenesis. The expression pattern of both OPG and OPGL during atherogenesis might suggest a regulatory role of these proteins not only in osteoclastogenesis but also in atherosclerotic calcification.

Adult↗
PubMed2006

Vascular calcification in chronic kidney disease.

Vascular calcification is often encountered in advanced atherosclerotic lesions and is a common consequence of aging. Calcification of the coronary arteries has been positively correlated with coronary atherosclerotic plaque burden, increased risk of myocardial infarction, and plaque instability. Chronic kidney disease (CKD) patients have two to five times more coronary artery calcification than healthy age-matched individuals. Vascular calcification is a strong prognostic marker of cardiovascular disease mortality in CKD patients. Vascular calcification has long been considered to be a passive, degenerative, and end-stage process of atherosclerosis and inflammation. However, recent evidence indicates that bone matrix proteins such as osteopontin, matrix Gla protein (MGP), and osteocalcin are expressed in calcified atherosclerotic lesions, and that calcium-regulating hormones such as vitamin D3 and parathyroid hormone-related protein regulate vascular calcification in in vitro vascular calcification models based on cultured aortic smooth muscle cells. These findings suggest that vascular calcification is an actively regulated process similar to osteogenesis, and that bone-associated proteins may be involved in the development of vascular calcification. The pathogenesis of vascular calcification in CKD is not well understood and is almost multifactorial. In CKD patients, several studies have found associations of both traditional risk factors, such as hypertension, hyperlipidemia, and diabetes, and uremic-specific risk factors with vascular calcification. Most patients with progressive CKD develop hyperphosphatemia. An elevated phosphate level is an important risk factor for the development of calcification and cardiovascular mortality in CKD patients. Thus, it is hypothesized that an important regulator of vascular calcification is the level of inorganic phosphate. In order to test this hypothesis, we characterized the response of human smooth muscle cell (HSMC) cultures to inorganic phosphate levels. Our findings indicate that inorganic phosphate directly regulates HSMC calcification through a sodium-dependent phosphate transporter mechanism. After treatment with elevated phosphate, there is a loss of smooth muscle lineage markers, such as alpha-actin and SM-22alpha, and a simultaneous gain of osteogenic markers such as cbfa-1 and osteocalcin. Elevated phosphate may directly stimulate HSMC to undergo phenotypic changes that predispose to calcification, and offer a novel explanation of the phenomenon of vascular calcification under hyperphosphatemic conditions. Furthermore, putative calcification inhibitory molecules have been identified using mouse mutational analyses, including MGP, beta-glucosidase, fetuin-A, and osteoprotegerin. Mutant mice deficient in these molecules present with enhanced cardiovascular calcification, demonstrating that specific molecules are normally important in suppressing vascular calcification. These findings suggest that the balance of inducers, such as phosphate, and inhibitors, such as MGP, fetuin-A, and others, are likely to control whether or not calcification occurs under pathological conditions.

Alkaline Phosphatase↗
PubMed2005

Analysis of gene expression in non-regressed and regressed bovine corpus luteum tissue using a customized ovarian cDNA array.

The lifespan of the bovine corpus luteum (CL) is an important factor in the control of normal ovarian cyclicity and the establishment and maintenance of pregnancy. There is increasing evidence that CL lifespan is regulated by alternative expression of genes that promote or inhibit luteolysis. To gain further insights into these events a 434 character ovarian cDNA array comprising genes attributed to key aspects of CL function including more than 100 anonymous expressed sequence tags (ESTs) was constructed and screened with alpha(33)P dATP labeled RNA isolated from non-regressed (n=6) and regressed (n=6) CL tissue. Significance analysis of microarrays (SAM) identified 15 genes that changed expression 1.7-fold or more with a false discovery rate of <5%. The differentially expressed genes encoded enzymes involved in steroid biosynthesis and oxygen radical metabolism and proteins involved in extracellular matrix remodeling, apoptosis and cell structure. Results for five of the differentially expressed genes including matrix gla protein and collagen alpha1(I) (extracellular matrix), glutathione-S-transferase alpha I (oxygen metabolism), clusterin (apoptosis) and scavenger receptor BI (steroid biosynthesis) were confirmed by Northern blot analysis and found to be significantly different (P<0.01) between non-regressed and regressed CL tissue. Collectively this study identified genes with recognized roles in CL regression, genes with potential roles in this process and genes whose function have yet to be defined in this event.

Animals↗
PubMed1999

[Vitamin K].

It is well-known that vitamin K has a strong blood coagulation activity by acting a cofactor for gamma-carboxylase which catalizes the conversion of specific glutamic acid residue to gamma-carboxyglutamic acid residue (Gla). Some of the Gla-containing proteins, such as osteocalcin and matrix Gla protein have been found in calcifying tissues. These proteins are considered to play an important role in Ca-deposition. Recent studies have clearly demonstrated the substantial role of vitamin K in bone metabolism that has been developed for clinical use. Furthermore, diverse physiological activities have been found subsequently as follows: regulation of glucose metabolism, anti-arteriosclerosis, and induction of cell differentiation. Here I introduce the mainly physiological activities of vitamin K2, making a comparison with vitamin K1.

Arteriosclerosis↗
PubMed1991

Direct identification of gamma-carboxyglutamic acid in the sequencing of vitamin K-dependent proteins.

We report the first direct method for the identification of the vitamin K-dependent Ca2+ binding amino acid, gamma-carboxyglutamic acid (Gla), in the sequencing of proteins. The carboxyl groups on the protein are first converted to methyl esters with methanolic HCl, a procedure that reduces the polarity of the resulting ATZ derivative of dimethyl-Gla and so greatly improves its extraction from the polybrene-treated glass fiber filter. After conversion to the PTH derivative in methanolic HCl, the resulting dimethyl ester of PTH Gla can be identified directly by a simple modification of the standard HPLC program for the separation of PTH derivatives. This methylation procedure can be used to identify Gla residues in proteins bound to PVDF membranes, as we demonstrate for matrix Gla protein and prothrombin, and to evaluate directly the degree of partial gamma-carboxylation at given glutamic acid residues, as we demonstrate for the 50% gamma-carboxylation of residue 17 in human bone Gla protein.

1-Carboxyglutamic Acid↗
PubMed2003

Osteo/chondrocytic transcription factors and their target genes exhibit distinct patterns of expression in human arterial calcification.

OBJECTIVE: Mineralization-regulating proteins are found deposited at sites of vascular calcification. However, the relationship between the onset of calcification in vivo and the expression of genes encoding mineralization-regulating proteins is unknown. This study aimed to determine the temporal and spatial pattern of expression of key bone and cartilage proteins as atherosclerotic calcification progresses. METHODS AND RESULTS: Using reverse transcription-polymerase chain reaction on a panel of noncalcified and calcified human arterial samples, two classes of proteins could be identified: (1) Matrix Gla protein, osteonectin, osteoprotegerin, and aggrecan were constitutively expressed by vascular smooth muscle cells (VSMCs) in the normal vessel media but downregulated in calcified arteries whereas (2) alkaline phosphatase, bone sialoprotein, osteocalcin, and collagen II were expressed predominantly in the calcified vessel together with Cbfa1, Msx2, and Sox9, transcription factors that regulate expression of these genes. In the calcified plaque in situ hybridization identified subsets of VSMCs expressing osteoblast and chondrocyte-like gene expression profiles whereas osteoclast-like macrophages were present around sites of calcification. CONCLUSIONS: These observations suggest a sequence of molecular events in vascular calcification beginning with the loss of expression by VSMCs, of constitutive inhibitory proteins, and ending with expression by VSMCs and macrophages of chondrocytic, osteoblastic, and osteoclastic-associated proteins that orchestrate the calcification process.

Calcinosis↗
PubMed2003

Biochemical characterization of the serum fetuin-mineral complex.

The present study was carried out to characterize the fetuin-mineral complex (FMC), a high molecular mass complex of calcium phosphate mineral and the proteins fetuin and matrix Gla protein (MGP) that was initially discovered in serum of rats treated with etidronate and appears to play a critical role in inhibiting calcification in vivo. Fetuin purified from the FMC contains 3.3 mol of protein-bound phosphate. There is 1.3 mg of FMC/ml of serum 6 h after etidronate injection, and the FMC is 46% fetuin and 53% mineral by mass. Formation of the FMC in the first 6 h after etidronate injection does not increase serum fetuin despite the fact that 50% of serum fetuin is associated with the FMC, and clearance of the FMC in the 9-24-h interval lowers total serum fetuin by 50%. These observations suggest that the fetuin component of the FMC is derived from fetuin initially in serum and that clearance of the FMC removes the associated fetuin from circulation. One additional protein was consistently present in all preparations of the FMC, spp24 (secreted phosphoprotein 24). This 24-kDa protein is similar in domain structure to fetuin and, like fetuin and MGP, contains several residues of phosphoserine and accumulates in bone. Exogenous spp24 associated strongly with the FMC when added to serum containing it. These observations suggest that spp24 may, like fetuin and MGP, play a role in inhibiting calcification.

Animals↗
PubMed2003

The inhibition of calcium phosphate precipitation by fetuin is accompanied by the formation of a fetuin-mineral complex.

The present studies show that the previously reported ability of fetuin to inhibit the precipitation of hydroxyapatite from supersaturated solutions of calcium and phosphate in vitro is accompanied by the formation of the fetuin-mineral complex, a high molecular mass complex of calcium phosphate mineral and the proteins fetuin and matrix Gla protein that was initially discovered in the serum of rats treated with etidronate and that appears to play a critical role in inhibiting calcification in vivo. Rat serum potently inhibited the precipitation of calcium phosphate mineral when the concentration of calcium and phosphate were increased by 10 mm each, and the modified serum was incubated at 37 degrees C for 9 days; in the absence of serum, precipitation occurred in seconds. Large amounts of the fetuin-mineral complex were generated in the first 3 h of this incubation and remained throughout the 9-day incubation. Purified bovine fetuin inhibited the precipitation of mineral for over 14 days in a solution containing 5 mM calcium and phosphate at pH 7.4 at 22 degrees C, whereas precipitation occurred in minutes without fetuin. There was a biphasic drop in ionic calcium in the fetuin solution, however, from 5 to 3 mM in the first hour and from 3 to 0.9 mM between 20 and 24 h; these changes in ionic calcium are due to the formation of complexes of calcium, phosphate, and fetuin. The complex found at 24 h to 14 days is identical to the fetuin-mineral complex found in the serum of etidronate-treated rats, whereas the complex found between 1 and 20 h is less stable.

Animals↗
PubMed2002

[Vascular calcification and bone-related factors].

Bone is consisted of bone matrix proteins produced by osteoblasts and minerals, Recently, it has been reported that bone-related factors are also involved in vascular calcification. Among bone matrix proteins, osteopontin and matrix Gla protein play important roles in vascular calcification. Regulatory factors for osteoblast differentiation (BMP) and osteoclast differentiation (osteoprotegerin) are also involved in vascular calcification.

English Abstract↗
PubMed1990

The metabolic functions and mechanism of action of vitamin K.

Vitamin K functions in animal cells as the cofactor of the enzyme vitamin K-dependent carboxylase which catalyzes the post-translational formation of gamma-carboxyglutamyl (Gla) residues in specific vitamin K-dependent proteins. These proteins include four blood coagulation factors (prothrombin and Factors VII, IX and X), other plasma proteins (protein C, protein S and protein Z), two proteins from bone (osteocalcin or bone Gla-protein and matrix Gla-protein), and other proteins from lung, kidney, spleen, testis, placenta and other tissues. In the proteins involved in blood coagulation the Gla residues are mandatory for the activation of the inactive proenzymes; this process occurs on phospholipid surfaces to which the proenzymes are bound via Gla residues and calcium ions. The energy needed in the carboxylation reaction is obtained from the oxidation of vitamin K hydroquinone to 2,3-epoxide of the vitamin. Specific enzymes, vitamin K epoxide reductase and vitamin K quinone reductases, catalyze consecutive reactions in which the vitamin K hydroquinone is regenerated, thus allowing continued use of the vitamin K molecule for the carboxylations. The oral anticoagulants, derivatives of 4-hydroxycoumarin and indan-1,3-dione, used as therapeutic agents in thromboembolic disease, are antagonists to vitamin K preventing the catalytic use of vitamin K in the carboxylations by irreversibly inhibiting vitamin K epoxide reductase.

Animals↗
PubMed1997

Skeletal functions of vitamin K-dependent proteins: not just for clotting anymore.

Osteocalcin and matrix Gla protein (MGP) are two vitamin K-dependent proteins present in bone and cartilage. Transgenic mice models were recently developed to isolate the function of each of these proteins. While osteocalcin-deficient mice have increased bone formation, MGP-deficient mice have abnormal calcification leading to osteopenia, fractures, and premature death owing to arterial calcification.

Animals↗
PubMed2002

The involvement of matrix glycoproteins in vascular calcification and fibrosis: an immunohistochemical study.

Calcification and fibrointimal proliferation are associated with advanced complicated atherosclerosis in large arteries but may also occur in smaller vessels, resulting in ischaemic tissue necrosis. This study investigates whether the mechanisms of calcification and intimal fibrosis are similar in vessels of different sizes. The localization of osteopontin (OPN), matrix Gla protein (MGP), thrombospondin-1 (TSP-1), and cartilage oligomeric matrix protein (COMP) was investigated in three types of human vascular lesions: atherosclerosis, chronic vascular rejection (CVR) in renal allografts, and calcific uraemic arteriolopathy (calciphylaxis). These lesions were chosen as they affect different sized blood vessels and they exhibit a fibroproliferative intimal reaction, with or without calcification, resulting in luminal obliteration and ischaemic complications. OPN, MGP, TSP-1, and COMP were not detected in normal blood vessels. However, OPN and MGP were expressed at sites of calcification within atherosclerotic lesions and in microvessels in calciphylaxis, suggesting that calcification in different sized vessels may occur by a common mechanism. These proteins were not detected in areas of fibrointimal proliferation. In contrast, TSP-1 was localized primarily within the fibrous tissue of atherosclerotic lesions and was also expressed in the expanded fibrous intima of arteries showing CVR. COMP was localized primarily within the fibrous tissue under the lipid core of the majority of advanced atherosclerotic lesions. TSP-1 and COMP were also detected in areas of microcalcification in atherosclerotic lesions and TSP-1 was detected adjacent to areas of calcification in calciphylaxis. However, neither TSP-1 nor COMP was localized to calcific foci within these lesions. The localization of OPN, MGP, TSP-1, and COMP to pathological, but not normal arterial intima supports a pathogenetic role for these proteins in the development of vascular fibrosis and calcification. Modulation of their production and activity may offer a novel approach to the therapy of a number of vascular diseases.

Adult↗
PubMed2005

Relation of oral anticoagulation to cardiac valvular and coronary calcium assessed by multislice spiral computed tomography.

Vitamin K antagonists, known as oral anticoagulants, affect the synthesis and function of the matrix Gla protein, which is a potent inhibitor of tissue calcification. We performed multislice spiral computed tomography in 86 patients (53 men, mean age 71 +/- 8 years) with calcific aortic valve disease to quantitate the amount of calcification in the aortic valve and coronary arteries. Patients with long-term oral anticoagulation therapy (mean duration 88 +/- 113 months; n = 23) were compared with those without anticoagulation (n = 63). No differences were found in the demographic, clinical, or echocardiographic characteristics between the 2 study groups. Patients on oral anticoagulant therapy had increased coronary calcium (coronary Agatston score 1,561 +/- 1,141 vs 738 +/- 978, respectively; p = 0.024) and valvular calcium (valvular Agatston score 2,410 +/- 1,759 vs 1,070 +/- 1,085, respectively; p = 0.002) compared with patients without anticoagulation treatment. The results of our study have demonstrated that oral anticoagulation may be associated with increased valvular and coronary calcium in patients with aortic valve disease, presumably due to decreased activation of the matrix Gla protein.

Administration, Oral↗
PubMed2001

Arterial calcification: a review of mechanisms, animal models, and the prospects for therapy.

The causes of arterial calcification are beginning to be elucidated. Macrophages, mast cells, and smooth muscle cells are the primary cells implicated in this process. The roles of a variety of bone-related proteins including bone morphogenetic protein-2 (BMP-2), matrix Gla protein (MGP), osteoprotegerin (OPG), osteopontin, and osteonectin in regulating arterial calcification are reviewed. Animals lacking MGP, OPG, smad6, carbonic anhydrase isoenzyme II, fibrillin-1, and klotho gene product develop varying extents of arterial calcification. Hyperlipidemia, vitamin D, nicotine, and warfarin, alone or in various combinations, produce arterial calcification in animal models. MGP has recently been discovered to be an inhibitor of bone morphogenetic protein-2, the principal osteogenic growth factor. Many of the forces that induce arterial calcification may act by disrupting the essential post-translational modification of MGP, allowing BMP-2 to induce mineralization. MGP requires gamma-carboxylation before it is functional, and this process uses vitamin K as an essential cofactor. Vitamin K deficiency, drugs that act as vitamin K antagonists, and oxidant stress are forces that could prevent the formation of GLA residues on MGP. The potential role of arterial apoptosis in calcification is discussed. Potential therapeutic options to limit the rate of arterial calcification are summarized.

Animals↗
PubMed2006

Vitamin K deficiency reduces testosterone production in the testis through down-regulation of the Cyp11a a cholesterol side chain cleavage enzyme in rats.

Vitamin K (K) is an essential factor for the posttranslational modification of blood coagulation factors as well as proteins in the bone matrix (Gla proteins). It is known that K is not only distributed in the liver and bones but also abundantly distributed in the brain, kidney, and gonadal tissues. However, the role of K in these tissues is not well clarified. In this study, we used DNA microarray and identified the genes whose expression was affected in the testis under the K-deficient (K-def) state. The expression of genes involved in the biosynthesis of cholesterol and steroid hormones was decreased in the K-def group. The mRNA levels of Cyp11a - a rate-limiting enzyme in testosterone synthesis - positively correlated with the menaquinone-4 (MK-4) concentration in the testis. Moreover, as compared to the control (Cont) and K-supplemented (K-sup) groups, the K-def group had decreased testosterone concentrations in the plasma and testis. These results suggested that K is involved in steroid production in the testis through the regulation of Cyp11a.

Alkyl and Aryl Transferases↗