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PubMed2005

[Current concepts of vascular calcification].

Vascular calcification, such as coronary and aortic calcification, is a significant feature of vascular pathology. Two distinct forms of vascular calcification are well recognized. One is medial calcification, which occurs between the cell layers of smooth muscle cells, and is related to aging, diabetes and chronic renal failure. The other is atherosclerotic calcification, which occurs in the intima during the development of atheromatous disease. It has been shown that statins inhibit the progression of calcification in the aortic valve and the coronary artery. We have found that statins inhibit calcification of human aortic smooth muscle cells, which is induced by incubating the cells in high-phosphate medium. We also found that this is mediated by inhibiting cellular apoptosis, an essential mechanism for calcification, not by inhibiting inorganic phosphate (Pi) uptake by sodium-dependent phosphate cotransporter (NPC). Besides apoptosis and Pi uptake, such proteins as osteoprotegerin (OPG), matrix Gla protein (MGP), Klotho, fetuin-A, and apoE have been shown to negatively affect vascular calcification. Many previous reports suggest that vascular calcification appears to be regulated by promoting factors, such as Pi, apoptosis, modified LDL, advanced glycation end products, oxidative stress, vitaminD3, glucocorticoid, cbfa-1, osteopontin, and inhibitory factors, such as OPG, MGP, Klotho, fetuin-A, PTH/PTHrP, pyrophosphate, statins, and bisphosphonates. The precise mechanism of vascular calcification is of interest.

Animals↗
PubMed2000

Regulatory mechanisms in vascular calcification.

Vascular calcification is increasingly recognized as a significant contributor to cardiovascular morbidity and mortality as well as a biologically regulated process potentially subject to prevention and reversal. Both coronary and aortic calcification are common and influence plaque rupture, angioplasty and surgical complications, and compensatory enlargement. Aortic calcification increases aortic rigidity and contributes to cadiac ischemia, left ventricular hypertrophy, heart failure, and stroke. Calcification is also common in aortic valve leaflets further compounding adverse hemodynamic effects. Vascular calcification has often been attributed to "passive" crystallization. However, functional similarities between atherosclerotic lesions and bone contradict this view and indicate that it is no more "passive" than in embryonic bone formation or bone repair. Similarities include presence of all the major components of bone osteoid, bone regulatory factors, and subpopulations of artery wall cells that retain osteoblastic lineage potential. Several animal models for vascular calcification are available. Spontaneous vascular calcification occurs in null mice for matrix GLA protein (MGP), a small matrix protein of unknown function, and osteoprotegerin (OPG), known to modulate osteoclast differentiation. Vascular calcification may also be induced by feeding vitamin D and calcium or warfarin to normal animals, or by fat-feeding mice null for apoE or the LDL-receptor. Overall, regulation of vascular calcification is a growing field with surprising mechanisms and connections to other fields of biology.

Animals↗
PubMed1995

Gene expression and vascular smooth muscle cell phenotype.

Vascular smooth muscle cells (VSMCs) are involved in a number of vascular disease processes including hypertension and atherosclerosis. However, their role in the pathogenesis of vascular disease is largely undetermined. We and others have studied rat VSMCs in cell culture as a model for VSMC behaviour in vivo. In recent experiments we have applied molecular biological techniques to compare genes expressed by normal contractile VSMCs with those expressed by VSMCs which have undergone several passages in cell culture. Using differential screening of a cDNA library derived from cultured rat aortic VSMC RNA we identified seven genes which are preferentially expressed by contractile VSMCs; alpha-smooth muscle actin, gamma-smooth muscle actin, calponin, phospholamban, tropoelastin, SM22 alpha and CHIP28, and two which are preferentially expressed in passaged cells which have down-regulated their contractile proteins; osteopontin (OP) and matrix Gla protein (MGP). In situ hybridization studies have confirmed that calponin and SM22 alpha, are highly expressed by medial VSMCs in human coronary arteries with little or no expression in the atheromatous intima whilst the converse is true for OP and MGP. Studies by ourselves and others have confirmed that OP is a marker for proliferating rat VSMCs both in vitro and in vivo. However, the evidence that OP is expressed by proliferating human VSMCs is less convincing.

Animals↗
PubMed1998

Impaired expression of noncollagenous bone matrix protein mRNAs during fracture healing in ascorbic acid-deficient rats.

In scorbutic patients, fractures are slow to heal because of impaired collagen synthesis. To investigate the influence of impaired collagen synthesis on the differentiation and proliferation of osteogenic and chondrogenic cells, we examined the expression of genes encoding bone matrix proteins, including osteonectin (ON), osteopontin (OPN), osteocalcin (OC), and matrix Gla protein (MGP), as differentiation markers for osteogenic and chondrogenic cells during fracture healing in Osteogenic Disorder Shionogi (ODS) rats, which have a hereditary defect in the ability to synthesize ascorbic acid (Asc). In ODS rats without Asc supplementation, intramembranous ossification was completely inhibited. Although a few fibroblast-like cells expressing ON mRNA were observed, no OPN mRNA-expressing cells were detected. During endochondral ossification, a small amount of metachromatic staining cartilage appeared at the fracture site, but there was no provisional calcification zone in the cartilage. Chondrocytes expressed ON and MGP mRNAs, but not OPN mRNA. When Asc was given to these rats, callus formation was soon detected around the fracture site, while OPN mRNA was expressed by differentiated osteoblasts and hypertrophic chondrocytes. Our data indicate that impaired collagen synthesis due to Asc deficiency inhibited the increase of ON and MGP mRNA-expressing cells as well as the appearance of OPN mRNA-expressing cells. Since OPN is considered to play an important role in normal and pathological mineralization, lack of OPN mRNA expression accompanying impaired collagen synthesis may have a role in defective mineralization and delayed fracture healing in scurvy.

Animals↗
PubMed1993

Effects of ascorbic acid, calcitriol, and retinoic acid on the differentiation of preosteoblasts.

The responses of the immortalized rat preosteoblast UMR-201-10B to ascorbic acid (AA), 1,25(OH)2D3 (calcitriol), and retinoic acid (RA) were examined. UMR-201-10B cells have an undetectable basal alkaline phosphatase (ALP) activity that is induced after 24 h of treatment with 10(-6) M RA (4.64 +/- 0.06 mumol/h/mg of protein). The addition of 10(-8) M calcitriol resulted in a slight induction of ALP activity after 72 h (0.43 +/- 0.07 mumol/h/mg of protein). When calcitriol was added to RA, however, over the same period ALP activity was enhanced significantly compared with treatment with RA alone (RA and calcitriol, 12.29 +/- 0.86 mumol/h/mg of protein). Treatment with AA (50 micrograms/ml) alone had no effect on ALP activity but increased RA-induced ALP activity to 6.78 +/- 0.28 mumol/h/mg of protein at 24 h. In contrast, AA inhibited calcitriol-induced ALP activity after 7 days of combined treatment with calcitriol (calcitriol, 7.73 +/- 0.16 mumol/h/mg of protein; AA and calcitriol, 1.44 +/- 0.06 mumol/h/mg of protein). Individually, RA and calcitriol induced mRNA expression for ALP, matrix-gla protein (MGP), and osteopontin (OP). The steady state level of pro-alpha 1(I) collagen mRNA also was increased significantly by treatment with RA and AA individually. The combination of RA and calcitriol had a synergistic effect on ALP, OP, and especially MGP mRNA expression but significantly reduced the expression of pro-alpha 1(I) collagen mRNA. AA enhanced the effect of RA on the expression of pro-alpha 1(I) collagen, MGP, and ALP mRNAs as well as the effect of calcitriol on OP and MGP. The addition of AA to RA resulted in a decrease in the steady state level of OP, whereas its cotreatment with calcitriol caused a decrease in pro-alpha 1(I) collagen and ALP mRNA. In conclusion, these studies identify RA, calcitriol, and AA as regulators of differentiated osteoblast function.

Alkaline Phosphatase↗
PubMed1995

Alterations of bone matrix protein mRNA expression in rat aorta in vitro.

We examined the expression of matrix Gla protein (MGP), osteopontin (OPN), and osteonectin (ON) mRNAs in aortic rings excised from 3-month-, 10-month-, and 2-week-old rats during 72-hour incubations in serum-free media. In the aortic rings from 3-month-old rats, the expression of MGP mRNA was strong before incubation and increased during the 72-hour incubation. The expression of OPN mRNA was first detected after a 5-hour incubation and increased thereafter, and that of ON mRNA was strong before the incubation and decreased during the incubation. The expression of MGP and OPN mRNAs in 10-month- and 2-week-old rats was similar to that in 3-month-old rats. In contrast, expression of ON mRNA in 10-month-old rats and the expression of ON mRNA in 2-week-old rats was stronger than that in 3-month-old rats at every incubation period. In situ hybridization and immunohistochemistry identified the MGP, OPN, and ON mRNA-expressing cells as vascular smooth muscle cells. These results suggest that the expression of these mRNAs was regulated in incubation time-dependent and age-specific ways. We believe that this organ culture model is useful for further studies of the function of these bone matrix proteins and regulation of their expression in the vessel wall.

Animals↗
PubMed2005

A novel MGP mutation in a consanguineous family: review of the clinical and molecular characteristics of Keutel syndrome.

Keutel syndrome (KS) [OMIM 245150] is a rare autosomal recessive condition, characterized by abnormal cartilage calcification. Mutations in the matrix Gla protein gene (MGP) have been previously reported in three unrelated KS families. MGP is an extracellular matrix protein that acts as a calcification inhibitor by repressing bone morphogenetic protein 2 (BMP2). Loss-of-function mutations of MGP result in abnormal calcification of the soft tissues, a cardinal feature of KS. We report the fourth MGP mutation (IVS2 + 1G > A) in a consanguineous Arab family, which results in the loss of the consensus donor splice site at the exon 2-intron 2 junction. In addition to the typical manifestations, we observed abnormalities in the white matter of the brain, optic nerve atrophy, and mid-dermal elastolysis in the affected individuals of this family. This report broadens the clinical phenotype observed in patients with KS. The effect of the IVS2 + 1G > A mutation is consistent with the previously reported loss-of-function mutations of MGP.

Abnormalities, Multiple↗
PubMed1995

Expression of bone-related protein messenger RNA in human meningiomas: possible involvement of osteopontin in development of psammoma bodies.

Meningiomas often contain concentric calcified foci, referred to as psammoma bodies. Since calcium phosphate deposits in both psammoma bodies and bone tissues, we examined whether messenger (m) RNA of bone-related extracellular matrix proteins and bone morphogenetic proteins (BMP) were expressed in human meningioma tissues. Northern blotting demonstrated the expression of osteopontin (OPN), matrix Gla protein (MGP), osteonectin (ON) and BMP-4 mRNA but not bone sialoprotein, osteocalcin and BMP-2 mRNA. In situ hybridization revealed that most OPN mRNA-expressing cells were located around the psammoma bodies in meningothelial whorls. Moreover, combination of in situ hybridization and immunohistochemistry on serial sections showed that the OPN mRNA-expressing cells were CD68-positive, suggesting they were macrophages. Immunohistochemistry with anti-OPN antibody and von Kossa staining on the adjacent section showed that the deposition site of OPN protein was consistent with that of calcium phosphate. Neither MGP nor ON mRNA expression appeared to correlate with the calcification. The present result suggests that OPN produced by CD68-positive macrophages may play a significant role for development of psammoma bodies in meningiomas.

Antibodies, Monoclonal↗
PubMed1995

Role of vitamin K in bone metabolism.

Vitamin K is a cofactor required for the formation of gamma-carboxyglutamate (Gla) residues in proteins. Osteoblasts produce at least three different Gla-containing proteins: osteocalcin, matrix Gla-protein, and protein S. After cellular secretion of these proteins, the main part of each remains bound to the hydroxyapatite matrix in bone, but their function remains unclear. Part of the newly synthesized osteocalcin is also set free into the bloodstream, where it may be used as a diagnostic marker for bone formation. Several studies have demonstrated that a poor vitamin K status is associated with an increased risk of osteoporotic bone fractures. Whether vitamin K supplementation will reduce the rate of bone loss in postmenopausal women remains a matter of debate.

Animals↗
PubMed2001

Discovery of a high molecular weight complex of calcium, phosphate, fetuin, and matrix gamma-carboxyglutamic acid protein in the serum of etidronate-treated rats.

In the present study we report the discovery of a novel protein-mineral complex in the serum of rats treated with doses of the bone-active bisphosphonate etidronate that inhibit normal bone mineralization. The composition of this high molecular mass protein-mineral complex consists of about 18% mineral, 80% fetuin, and 2% matrix Gla protein (MGP) by weight, and the presence of the complex in serum after an injection of 8 mg etidronate/100 g of body weight elevates calcium by 1.8-fold (to 4.3 mm), phosphate by 1.6-fold (to 5.6 mm), and MGP by 25-fold (to 12 microg/ml). The serum mineral complex reaches maximal levels at 6 h after subcutaneous injection of etidronate and is subsequently cleared from serum by 24 h. This highly specific complex of fetuin, MGP, and mineral prevents the growth, aggregation, and precipitation of the mineral component, which indicates that the previously reported calcification inhibitory activities of fetuin and MGP may be related to their ability to form stable complexes with nascent mineral nuclei. Treatment with the vitamin K-antagonist warfarin prevents the increase in serum MGP after etidronate injection, which shows that the increase in serum MGP is due to new synthesis and that the gamma-carboxylation of MGP is necessary for its binding to the serum mineral complex.

Animals↗
PubMed1999

Expression of bone matrix proteins in urolithiasis model rats.

Urinary calcium stones are a pathological substance, and they show similarities to physiological mineralization and other pathological mineralizations. The expression of messenger (m) RNAs of osteopontin (OPN), matrix Gla protein (MGP), osteonectin (ON) and osteocalcin (OC) in bones and teeth has been described. We previously identified OPN as an important stone matrix protein. In addition, the spontaneous calcification of arteries and cartilage in mice lacking MGP was recently reported, a finding which indicates that MGP has a function as an inhibitor of mineralization. Here, we examined the mRNA expressions of OPN, MGP, ON, and OC in the kidneys of stone-forming model rats administered an oxalate precursor, ethylene glycol (EG) for up to 28 days. The Northern blotting showed that the mRNA expressions of OPN and MGP were markedly increased with the administration of EG, but their expression patterns differed. The OPN mRNA expression reached the maximal level at day 7 after the initiation of the EG treatment and showed no significant difference after 14 and 28 days, whereas the MGP mRNA expression rose gradually to day 28. The in situ hybridization demonstrated that the cell type expressing OPN mRNA was different from that expressing MGP. We suggest that OPN acts on calcification and MGP acts on suppression.

Animals↗
PubMed2003

Deficiencies of calcium-regulatory proteins in dialysis patients: a novel concept of cardiovascular calcification in uremia.

Dialysis patients suffer a manifold increase in cardiovascular mortality when compared to a nonuremic population, while this phenomenon is not sufficiently explained by an increased prevalence of traditional risk factors, such as hypercholesterolemia and hypertension. The presence of hyperphosphatemia, of an increased calcium x phosphate product, as well as the magnitude of vascular and valvular calcifications, were recently identified as specific major risk factors of cardiovascular mortality in the uremic population. Furthermore, hyperphosphatemia and an increased calcium x phosphate product could be quantitatively linked to the burden of coronary artery calcification in young dialysis patients, suggesting the correction of hyperphosphatemia as the central target for preventive therapeutic intervention. Recent studies in knockout mice, however, point to the alternative possibility that deficiencies in calcium-regulatory proteins may represent important pathomechanisms leading to extraosseous calcifications. alpha 2-Heremans Schmid glycoprotein (Ahsg/fetuin) and matrix Gla protein (MGP) are strong inhibitors of calcification in vivo. Novel evidence that deficiencies of such proteins may be involved in the pathogenesis of cardiovascular calcifications in dialysis patients will be discussed.

Animals↗
PubMed1995

Type X collagen gene expression in mouse chondrocytes immortalized by a temperature-sensitive simian virus 40 large tumor antigen.

Mouse endochondral chondrocytes were immortalized with a temperature-sensitive simian virus 40 large tumor antigen. Several clonal isolates as well as pools of immortalized cells were characterized. In monolayer cultures at the temperature permissive for the activity of the large tumor antigen (32 degrees C), the cells grew continuously with a doubling time of approximately 2 d, whereas they stopped growing at nonpermissive temperatures (37 degrees C-39 degrees C). The cells from all pools and from most clones expressed the genes for several markers of hypertrophic chondrocytes, such as type X collagen, matrix Gla protein, and osteopontin, but had lost expression of type II collagen mRNA and failed to be stained by alcian blue which detects cartilage-specific proteoglycans. The cells also contained mRNAs for type I collagen and bone Gla protein, consistent with acquisition of osteoblastic-like properties. Higher levels of mRNAs for type X collagen, bone Gla protein, and osteopontin were found at nonpermissive temperatures, suggesting that the expression of these genes was upregulated upon growth arrest, as is the case in vivo during chondrocyte hypertrophy. Cells also retained their ability to respond to retinoic acid, as indicated by retinoic acid dose-dependent and time-dependent increases in type X collagen mRNA levels. These cell lines, the first to express characteristic features of hypertrophic chondrocytes, should be very useful to study the regulation of the type X collagen gene and other genes activated during the last stages of chondrocyte differentiation.

Animals↗
PubMed2004

New developments in our understanding of DISH (diffuse idiopathic skeletal hyperostosis).

PURPOSE OF REVIEW: Diffuse idiopathic skeletal hyperostosis (DISH) or Forestier's disease is a common disorder among older adults. The diagnosis is based solely on radiographic abnormalities defined using the Resnick criteria. DISH is characterized by ossification of the anterior longitudinal ligament of the spine and various extraspinal ligaments. DISH often coexists with OA, but patients affected by this disorder differ from patients with primary OA in several aspects: prevalence in the general population, gender distribution, anatomic site of primary involvement, magnitude and distribution in the spine and the peripheral joints. Purpose of this review is to summarize new clinical, pathogenetic and therapeutic insights of this disease. RECENT FINDINGS: Recent studies confirm that patients with DISH have a greater body mass index, higher serum uric acid levels and are more likely to have diabetes mellitus. In addition, DISH is most probably related to abnormal bone cell growth/activity reflecting the influence of metabolic factors that lead to new bone formation. Serum matrix Gla protein may be a marker of osteometabolic syndromes, such as DISH, that cause hyperostosis. SUMMARY: Many recent developments of DISH are described in this review. Possible pathogenetic mechanism driving bone deposition are discussed. DISH is still recognized radiographically; no specific drug has been yet identified.

Aged↗
PubMed2006

The elastic lamellae of devitalized arteries calcify when incubated in serum: evidence for a serum calcification factor.

OBJECTIVE: To determine whether serum contains an activity that induces artery calcification. METHODS AND RESULTS: The elastic lamellae of devitalized rat aortas calcify rapidly in rat or bovine serum, or in human serum provided [Pi] > or =2 mmol/L. This calcification is attributable to a potent serum calcification factor (SCF), one that causes devitalized aortas to calcify when incubated in DMEM containing as little as 1.5% serum but not in DMEM alone. The SCF that initiates medial elastin calcification has the same 50- to 150-kDa size and protease sensitivity as the SCF shown previously to initiate calcification of type I collagen. Our working hypothesis is that the same SCF initiates calcification of collagen and elastin, and that this SCF arises from sites of normal bone mineralization and, like alkaline phosphatase, is released into general circulation. The SCF does not initiate medial elastin calcification in living arteries, which suggests that vascular cells may prevent this calcification. This hypothesis is supported by the observations that living arteries secrete the calcification inhibitor matrix Gla protein (MGP); that inactivation of MGP with warfarin causes living arteries to calcify; and that addition of MGP to medium containing warfarin prevents this calcification. CONCLUSIONS: The elastic lamellae of devitalized aortas calcify rapidly in serum.

Animals↗
PubMed2003

[Calcification marker matrix G1a protein in patients with hyperlipidemia].

At the site of atherosclerotic plaque formation, proliferating vascular muscle cells express Matrix-Gla-protein (MGP) which depends on vitamin K and plays a regulatory role in tissue calcification. Measurements of MGP in serum showed significantly higher values in 66 patients with hyperlipidemia compared to healthy controls. MGP correlated with cholesterol, triglyceride, and low-density lipoprotein, but not with the adhesion molecule GMP-140. The evaluation of the patients' life and nutritional habits showed that nearly exclusively the patients who regularly consume fruit had low MGP values. Smokers had high MGP levels, three times higher than non-smokers. A decrease in MGP levels could be shown already three weeks after inpatient rehabilitation comprising therapeutic exercise and change in nutrition.

Adult↗
PubMed2001

Recent advances in multifactorial regulation of vascular calcification.

Calcification presents important clinical implications in cardiovascular diseases, especially in coronary arteries. Epidemiological evidence has shown the coexistence of vascular calcification with both atherosclerosis and osteoporosis, and increasing evidence has shown the role of hyperlipidemia and atherogenic phospholipids in vascular calcification. The etiology of vascular calcification is also increasingly recognized as an active process. Vascular calcification initiates with matrix vesicle formation and mineralization following a process similar to that in bone. In addition, many bone regulatory factors have been shown to be present in calcified atherosclerotic lesions. In this review, we focus on the new developments emerging during the past year in regulation of vascular calcification. Regulatory factors include matrix GLA protein, the phosphate cotransporter Pit-1, a calcium-sensing receptor related factor, osteoprotegerin, leptin, bisphosphonates and oxidized lipids. Some of these, including oxidized lipids, osteoprotegerin, and bisphosphonates, appear to regulate mineralization in both bone and vasculature and may account for the co-existence of osteoporosis and atherosclerotic calcification that is independent of age.

Animals↗
PubMed1988

1,25-Dihydroxyvitamin D3 stimulates the synthesis of matrix gamma-carboxyglutamic acid protein by osteosarcoma cells. Mutually exclusive expression of vitamin K-dependent bone proteins by clonal osteoblastic cell lines.

Several clonal rat osteosarcoma cell lines were tested for the ability to express and secrete matrix Gla protein (MGP), a small vitamin K-dependent protein found in bone and cartilage. Two independently derived cell lines, UMR 106-01 and ROS 25/1, expressed MGP mRNA and secreted MGP antigen identical in size with that found in bone. No MGP message could be detected in ROS 17/2 and 2/3 cells, cell lines previously shown to synthesize the other known vitamin K-dependent bone protein, bone Gla protein (BGP), and no BGP mRNA could be detected in the cell lines which synthesize MGP. Since UMR 106-01 and ROS 17/2 are presently the best characterized clonal osteoblastic cell lines, the discovery of the mutually exclusive expression of MGP and BGP by these cell lines indicates that osteosarcoma cells can be fixed in different phenotypic states and that MGP and BGP should be useful markers for the analysis of phenotypic expression in bone. Treatment of UMR 106-01 cells with 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) dramatically increased MGP mRNA within 4 h and, by 24 h, increased MGP secretion 15-fold. This is only the second example of a bone matrix protein whose synthesis is dramatically increased by vitamin D, the first being the 6-fold stimulation of BGP synthesis by 1,25(OH)2D3 in ROS 17/2 cells. The discovery that MGP and BGP are similarily regulated by 1,25(OH)2D3 was unexpected since the two proteins differ markedly in structure, physical properties, and tissue distribution. Since the synthesis of MGP is rapidly and dramatically increased by 1,25(OH)2D3, it is probable that MGP plays a role in the normal bone response to the hormone. MGP may also be the vitamin K-dependent protein whose abnormal synthesis in the Warfarin-treated animal modifies the bone response to 1,25(OH)2D3.

Animals↗