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PubMed2004

Regulatory role of endothelium in the expression of genes affecting arterial calcification.

Vascular calcification is a highly regulated process sharing features of bone mineralization. Since endothelium regulates many of the processes during atherogenesis, we monitored the expression of genes involved in calcification upon exposure of human coronary artery endothelial cells (HCAECs) to atherogenic stimuli. Genes studied were: core binding factor alpha-1 (Cbfa1/Runx2), a pivotal transcriptional regulator of osteogenesis; bone morphogenetic protein-2 (BMP2), an inducer of cartilage and bone; and matrix gla-protein (MGP), a potent inhibitor of calcification, which exerts its action by blocking BMP2. HCAECs were treated with oxidized-low density lipoprotein (ox-LDL, 80 microg/mL) or tumor necrosis factor-alpha (TNFalpha, 10 ng/mL), and the expression of Cbfa1, BMP2, and MGP was quantified by real-time PCR. Cbfa1 was expressed at low levels in untreated HCAECs, and its expression did not change with ox-LDL or TNFalpha treatment. The expression of BMP2 and MGP increased early after exposure to ox-LDL or TNFalpha (at 2-8 h), and the increase was not evident at 24 h. Ox-LDL exerted a stronger effect on MGP than on BMP2 expression. The effects of ox-LDL, but not TNFalpha, on MGP and BMP2 expression were inhibited by pretreatment of cells with an antibody directed at LOX-1, a lectin-like receptor for ox-LDL (10 microg/mL). Thus, the endothelium, when exposed to atherogenic stimuli, ox-LDL in particular, regulates the process of calcification by enhancing the expression of the bone inhibitory MGP, while the expression of Cbfa1 remains unchanged. Upregulation of BMP2 may represent a feedback upregulation in response to increase in MGP. The effect of ox-LDL appears to be mediated by LOX-1 activation.

Antibodies↗
PubMed1991

Bone protein and peptide assays in the diagnosis and management of skeletal disease.

The measurement in blood of bone proteins is an important adjunct to imaging procedures for clinical assessment of the skeleton. The discovery of new bone proteins and their structural characterization has led to immunochemical procedures of improved sensitivity and specificity for their quantification. An appreciation of the advantages and disadvantages of these evolving methodologies will assist in their clinical application.

Acid Phosphatase↗
PubMed1987

Metal binding and metal-induced conformational change of frog bone gamma-carboxyglutamic acid-containing protein.

Ca2+ or Cd2+ binding and the conformational change induced by the metal binding in two frog bone Gla-proteins (BGP, termed BGP-1 and BGP-2) were studied by equilibrium dialysis and CD measurement. By CD measurement in the far-ultraviolet region, the alpha-helix content of both apoBGPs was found to be 8%. Binding of both Ca2+ and Cd2+ was accompanied with a change in the CD spectrum, and the alpha-helix content increased to 15 and 25% for BGP-1 and BGP-2, respectively. CD measurement in the near-ultraviolet region indicated that the environment of aromatic amino acid residues in the protein molecule was changed by metal binding. Equilibrium dialysis experiments indicated that each of these two protein binds specifically 2 mol of Ca2+, and nonspecifically an additional 3-4 mol of Ca2+ in 0.02 M Tris-HCl/0.15 M NaCl (pH 7.4), at 4 degrees C. According to the two separate binding sites model, BGP-1 has 1 high-affinity Ca2+ binding site (Kd1 = 0.17 mM) and 1 low-affinity site (Kd2 = 0.29 mM), and BGP-2 contains 1 high-affinity site (Kd1 = 0.14 mM) and 1 low-affinity site (Kd2 = 0.67 mM). In addition, 2 Cd2+ bound to a high-affinity binding site on BGP-1 with Kd1 of 10.4 microM, and 1 Cd2+ bound to a low-affinity binding site with Kd2 of 41.5 microM. On the other hand, BGP-2 had three classes of binding sites and 1 Cd2+ bound to each binding site with Kd1 = 3.6 microM, Kd2 = 16.3 microM, Kd3 = 51.7 microM, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

1-Carboxyglutamic Acid↗
PubMed1990

The effect of food restriction and germ-free environment on age-related changes in bone matrix.

Studies were performed to determine the effects of food restriction or a germ-free environment on age-related changes in bone. Four groups of male Lobund-Wistar rats were examined at 6 months, 18 months, and 30 months of age. Conventional-free-fed rats were housed in routine laboratory cages and fed ad libitum. Conventional-restricted diet rats were fed 12 grams a day, which becomes restrictive at 8 weeks of age. Germ-free rats were maintained using gnotobiotic procedures and were free of pathogens. The germ-free rats were maintained on either the full-fed or restricted diet regimens. Serum bone Gla protein and matrix concentrations of calcium, magnesium, and hydroxyproline (reflecting collagen content) and bone Gla protein were not significantly different between the four treatment groups. All of these parameters except hydroxyproline, however, showed age-related declines in all four treatment groups. We conclude that prolongation of rat life span by dietary restriction and/or a germ-free environment did not alter the measured parameters in each age group, and did not alter or slow the age-related changes in the bone matrix.

Aging↗
PubMed1998

Adsorption of vitamin K-dependent blood coagulation proteins to spread phospholipid monolayers as determined from combined measurements of the surface pressure and surface protein concentration.

Spread phospholipid monolayers are particularly useful as model membranes in that changes in surface pressure (Deltapi) can be monitored in response to protein adsorption to the monolayer, thus providing a unique manner of assessing protein-membrane contact. In the present study, spread monolayers below their collapse pressures have been utilized to evaluate Ca2+-specific adsorption of several vitamin K-dependent coagulation proteins to monolayers that contain negatively charged phospholipid. From combined measurements of Deltapi and Gamma (the surface excess protein concentration), values of dGamma/dpi have been evaluated for different proteins with varying lipid composition of the monolayers. Using mixed, liquid-expanded monolayers at equivalent initial surface pressures (pii) and which contain different amounts of phosphatidylserine, phosphatidylcholine, and phosphatidylethanolamine, the dGamma/dpi of bovine prothrombin was shown to decrease monotonically with increasing protein affinity for the monolayer. For example, KD values of 7, 20, and 60 nM produced dGamma/dpi values of 14, 17, and 21 nmol m-1 mN-1, respectively. However, the trend in dGamma/dpi appears to originate from characteristics of the monolayer and not from those of the protein, since a much different adsorbate (i.e., a positively charged pyrene derivative) exhibited a similar trend in dGamma/dpi with monolayer composition. On the other hand, dGamma/dpi values of bovine prothrombin, human factor IX, human protein S, bovine protein C, and human protein C, determined using liquid-expanded phosphatidylserine monolayers, were essentially equivalent. Therefore, the five vitamin K-dependent proteins that were examined were equivalent in terms of the manner in which the gamma-carboxyglutamic acid (Gla) domain of each protein perturbed the surface pressure. This study shows that Ca2+-specific membrane contact sites in the Gla domain of the five proteins tested are similar despite the naturally occurring differences in the normal Gla domain sequence of these proteins.

Adsorption↗
PubMed1998

[Bone matrix proteins].

Bone matrix is composed of collagen and non-collagenous proteins. The collagen is mainly type I collagen. Characteristics of bone collagen are in posttranslational modifications and utilization of transcriptional elements in the promoter. The non-collagenous proteins are acidic Ca-binding proteins: bone Gla protein(BGP), bone sialoprotein (BSP), osteopontin, osteonectin etc. BGP and BSP are specific to bone, and other proteins are present also in non-mineralized tissues. BGP functions in suppression of excessive mineralization. BSP and osteopontin are sialoproteins containing a RGD cell-attachment sequence and poly(acidic amino acid) sequences. BSP is present in sites of bone formation. Osteopontin is involved in attachment of osteoclasts to bone surface.

Animals↗
PubMed1998

Evaluation of markers of bone and collagen turnover in patients with active and preclinical Cushing's syndrome and in patients with adrenal incidentaloma.

Although steroid-induced negative effects on bone and collagen have been well described in corticosteroid-treated patients, few studies have extensively evaluated bone and collagen turnover in patients with endogenous Cushing's syndrome. In this work serum bone-Gla protein (BGP), C-terminal cross-linked telopeptide of type I collagen (ICTP) and N-terminal propeptide of type III procollagen (PIIINP) levels were determined in patients with active (n = 12) and preclinical (n = 6) Cushing's syndrome, adrenal incidentalomas (n = 35) and in healthy controls (n = 28). In patients with overt Cushing's syndrome, serum BGP (0.9+/-0.2 ng/ml), ICTP (2.7+/-0.2 ng/ml) and PIIINP (1.9+/-0.2 ng/ml) levels were significantly lower (P < 0.0001) than in controls (5.5+/-0.2, 3.9+/-0.2 and 3.2+/-0.2 ng/ml respectively). In preclinical Cushing's syndrome, serum BGP (2.5+/-0.8 ng/ml), ICTP (2.2+/-0.1 ng/ml) and PIIINP (2.2+/-0.2 ng/ml) levels were significantly lower than in normal subjects (P < 0.0001, P < 0.0001 and P < 0.02 respectively), being similar to those recorded in overt Cushing's syndrome. In patients with adrenal incidentaloma, serum BGP (4.2+/-0.5 ng/ml) and ICTP (2.9+/-0.2 ng/ml) levels were significantly lower than those found in controls (P < 0.05 and P < 0.001 respectively), while serum PIIINP levels (3.6+/-0.2 ng/ml) did not differ from those of normals. In particular, 9/35 patients with adrenal incidentaloma had markedly depressed BGP levels (<2.0 ng/ml; mean 0.8+/-0.1 ng/ml): all patients of this subgroup showed an exaggerated 17-hydroxyprogesterone increase after ACTH administration. In the same patients, serum ICTP (3.0+/-0.4 ng/ml) and PIIINP (3.6+/-0.2 ng/ml) levels did not differ from those found in the incidentaloma group. In conclusion, our study indicates that bone and collagen turnover are markedly affected in patients with overt and preclinical Cushing's syndrome. Although patients with adrenal incidentaloma do not show any signs or symptoms of overt hypercortisolism, the presence of reduced BGP and ICTP levels might be considered a further index of an 'abnormal' pattern of steroid secretion in some of them. As a consequence, the presence of early alterations in markers of bone turnover might be useful for selecting those patients who need more accurate follow-up of the adrenal mass.

Adrenal Gland Neoplasms↗
PubMed1991

Effect of warfarin on early rat tooth development.

Rat pups were treated from birth to 5 days of age with the vitamin K antagonist warfarin in order to investigate possible functions of the vitamin K-dependent dentin Gla protein (DGP) in tooth development. Warfarin completely eliminated the immunocytochemically detectable DGP which is a prominent feature of dentin in control rat pups, and also caused an increased concentration of DGP in odontoblasts. Warfarin treatment did not affect the ultrastructure of cells or the extracellular matrix in the tooth germs. The width of the predentin layer, which is considered to be correlated with the rate of mineralization, was unchanged. These results are the first to demonstrate that warfarin treatment prevents the accumulation of DGP in dentin, and that the deposition of DGP has no influence on the overall rate of dentin matrix mineralization in tooth germs.

Animals↗
PubMed2005

The mechanism of calcium deposition in soft tissues.

The current understanding of the mechanisms of calcium deposition in soft tissues in chronic kidney disease (CKD) patients has been deeply investigated in the last ten years. Because of higher morbidity and mortality due to cardiovascular disease in dialysis patients compared to general population, several studies showed that extraskeletal calcification may play a major role in the pathogenesis of cardiovascular events in CKD patients. Traditionally, the pathogenesis of vascular and soft tissue calcification has been associated with a passive calcium-phosphate deposition. Actually, it is well known that extraskeletal calcification is also related to an active process. In this review, we analyzed some of the factors potentially involved in the pathogenesis of vascular calcification in CKD patients.

Activin Receptors, Type I↗
PubMed1999

Amino acids responsible for reduced affinities of vitamin K-dependent propeptides for the carboxylase.

The binding of the gamma-glutamyl carboxylase to its protein substrates is mediated by a conserved 18 amino acid propeptide sequence found in all vitamin K-dependent proteins. We recently found that the apparent affinities of the naturally occurring propeptides for the carboxylase vary over a 100-fold range and that the propeptide of bone Gla protein has severely impaired affinity for the carboxylase [Stanley, T. B., et al. (1999) J. Biol. Chem. 274, 16940-16944 (1)]. Here we report a consensus propeptide sequence that binds tighter (K(i) = 0.43 nM) to the carboxylase than any known propeptide sequence. Comparing the factor IX propeptide to the propeptides of protein C, bone Gla protein, and prothrombin, the weakest binding propeptides, allowed us to predict which residues might be responsible for these substrates' relatively weak binding to the carboxylase. We then made propeptides with the predicted amino acid changes and determined their binding affinities. The reduced binding affinity of these propeptides relative to that of FIX is due to residues -15 in protein C, -10 and -6 in bone Gla protein, and -9 in prothrombin. A role for the -9 position was not previously recognized but is further shown by our identification of a new, naturally occurring mutation at this position in factor IX which causes a warfarin-sensitive hemophilia B phenotype. In addition, we find that propeptides with mutations found in warfarin-sensitive patients have reduced affinity for the carboxylase, suggesting a physiological relevance of propeptide binding affinity.

Amino Acid Sequence↗
PubMed1997

Serum markers of bone metastases in postmenopausal breast cancer patients treated with formestane.

Bone metabolism marker evaluation is expected to play an auxiliary role in the diagnosis and follow-up of bone metastases in patients affected by different types of neoplasms. In this study we have evaluated osteoblastic and osteoclastic markers in 18 patients with bone metastases from breast cancer at diagnosis and for 1 year of follow-up during treatment with the aromatase inhibitor formestane. Osteoblastic markers include the carboxy-terminal propeptide of type I procollagen, the bone-specific alkaline phosphatase and the bone GLA protein. The carboxy-terminal cross-linked telopeptide of type I collagen (ICTP) was evaluated as a marker of osteoclastic activity. The patients were classified into three groups according to clinical response. A good correlation between marker level modifications and clinical evolution of skeletal metastases was observed for all the examined markers. Patients with progressive disease showed increasing levels of all markers, whereas patients in regression showed a reduction compared to the basal levels; patients with stable disease fell in between these two categories. We also found that basal ICTP values have prognostic significance: in the stable and progressive disease group they were higher than in the partial response group.

Alkaline Phosphatase↗
PubMed1998

Differentially expressed genes in C6.9 glioma cells during vitamin D-induced cell death program.

C6.9 rat glioma cells undergo a cell death program when exposed to 1, 25-dihydroxyvitamin D3 (1,25-D3). As a global analytical approach, we have investigated gene expression in C6.9 engaged in this cell death program using differential screening of a rat brain cDNA library with probes derived from control and 1,25-D3-treated cells. Using this methodology we report the isolation of 61 differentially expressed cDNAs. Forty-seven cDNAs correspond to genes already characterized in rat cells or tissues. Seven cDNAs are homologous to yeast, mouse or human genes and seven are not related to known genes. Some of the characterized genes have been reported to be differentially expressed following induction of programmed cell death. These include PMP22/gas3, MGP and beta-tubulin. For the first time, we also show a cell death program induced up-regulation of the c-myc associated primary response gene CRP, and of the proteasome RN3 subunit and TCTP/mortalin genes. Another interesting feature of this 1,25-D3 induced-cell death program is the down-regulated expression of transcripts for the microtubule motor dynein heavy chain/MAP 1C and of the calcium-binding S100beta protein. Finally 15 upregulated cDNAs encode ribosomal proteins suggesting a possible involvement of the translational apparatus in this cell program. Alternatively, these ribosomal protein genes could be up-regulated in response to altered rates of cellular metabolism, as has been demonstrated for most of the other isolated genes which encode proteins involved in metabolic pathways. Thus, this study presents to our knowledge the first characterization of genes which are differentially expressed during a cell death program induced by 1, 25-D3. Therefore, this data provides new information on the fundamental mechanisms which participate in the antineoplastic effects of 1,25-D3 and on the machinery of a cell death program in a glioma cell line.

Animals↗
PubMed2001

Mönckeberg's medial sclerosis and inorganic phosphate in uremia.

Mönckeberg's medial sclerosis (MMS) is one of the characteristic calcified lesions of uremic artery disease and often exhibits osseous metaplasia. Although its pathogenic mechanism is largely unknown, MMS may contain two different pathologic processes: degenerative process leading to apoptosis or necrosis of medial smooth muscle cells and osteogenic process leading to formation of bone-like structures. It has long been known that calcification follows necrosis. Apoptotic/necrotic cells often release matrix vesicles or membranous cellular degradation products resulting from disintegration of the cells that frequently serve as the nidus of calcification. On the other hand, vascular cells may exhibit osteoblastic phenotype in vitro, and some of the markers for osteoblastic differentiation and noncollagenous proteins regulating mineralization have been demonstrated in calcified arterial lesions. As a possible etiologic factor inducing these two responses, hyperphosphatemia among various metabolic disturbances recognized in uremia may play an important role in the development of MMS in uremia.

Animals↗
PubMed1988

Serum and urinary markers of bone remodeling: assessment of bone turnover.

It appears that at present, serum BGP is the one bone protein that has the most promise for assisting in the diagnosis and management of high turnover metabolic bone disease states. If further studies confirm its usefulness in osteoporosis as a predictor of rapid bone loss without the need for bone biopsy, this serum marker will then not only allow early detection but also an appropriate choice of therapy in osteoporosis, i.e. the use of specific inhibitors of high turnover states such as estrogen, calcitonin, or bisphosphonates. In addition, it may also permit more accurate follow-up of patients suffering from diseases such as primary hyperparathyroidism after surgery. In low turnover osteoporosis, it may also serve a useful function to observe whether the osteoblast can be stimulated to enhance bone formation with therapies such as fluoride, anabolic steroids, PTH, etc. As yet, additional measurements, such as bone histomorphometry and other bone mineral markers, are required for definitive diagnosis. Hopefully, the availability of specific well-characterized antibodies against BGP may define its role more accurately. Recently, several other new bone proteins have been identified but at present they have very limited clinical application. Future studies into the structure-function relationship of these bone proteins may identify those markers which will be most relevant to the diagnosis and treatment of metabolic bone disease.

1-Carboxyglutamic Acid↗
PubMed2005

Deficiencies of physiologic calcification inhibitors and low-grade inflammation in arterial calcification: lessons for cartilage calcification.

Apart from clinical parallels, similarities in the pathogenesis of arterial and articular cartilage calcification have come to light in recent years. These include the roles of aging, of chronic low-grade inflammation and of genetic and acquired dysregulation of inorganic pyrophosphate (PP(i)) metabolism. This review focuses on recent developments in understanding the pathogenesis of artery calcification pertinent to interpretation of the mechanistic basis for articular cartilage calcification in aging and osteoarthritis.

Arteries↗