Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.24.3 (collagenase)
18,340 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The thinning of the cornea that occurs in keratoconus has been well described; however, the mechanism of tissue degradation remains unknown. Elevated proteinase activity is one possibility and approximately 20 publications over the last 20 years have addressed this hypothesis. Early studies reported increased collagenase and gelatinase activities in the medium of keratoconus corneal cultures. After the characterization of the matrix metalloproteinase (MMP) enzymes, studies focused on the expression of specific MMPs, in particular the gelatinases, MMP-2 and MMP-9. Matrix metalloproteinase-2 was found to be the major MMP of the cornea and was constitutively produced in normal tissue, whereas MMP-9 expression was induced by various stimuli, including phorbol esters and even tissue culturing. These studies suggested that there were no differences in the amounts or states of activation of MMP between normal and keratoconus corneas, although the amounts of some proteinase inhibitors, including tissue inhibitors of metalloproteinases, alpha-1-proteinase inhibitor and alpha-2-macroglobulin, were decreased in keratoconus. Most recently, the lysosomal proteinases, cathepsin B and cathepsin G were reported to be elevated in keratoconus corneas, and it is possible that it was cathepsin activity, not MMP activity, that was measured in some early studies. Nevertheless, there are now about 20 human MMPs identified and it is possible that some of these, other than the well known collagenase (MMP-1) and gelatinases (MMP-2 and MMP-9), could be implicated in the pathology of keratoconus. Studies have begun to address more recently described MMPs and it has been reported that the membrane-bound MT1-MMP (MMP-14), which activates latent MMP-2, was found to have increased expression in keratoconus corneas, whereas the stromelysins, MMP-3 and MMP-10, were not.
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PMID:Is the corneal degradation in keratoconus caused by matrix-metalloproteinases? 1177

Dentine root caries is a process of demineralization and degradation of the organic matrix by proteinases. In this in situ study, the presence and activity of the matrix metalloproteinases 1, 2 and 9 (MMP-1, MMP-2, MMP-9) in saliva and in completely demineralized dentine specimens were investigated. Furthermore, the activity of cathepsin B was determined in saliva. A correlation between these enzymes and the level of degraded collagen was investigated. Demineralized dentine specimens were mounted in the partial prosthesis of 17 volunteers. Saliva samples were taken at 0, 2 and 4 weeks. After 4 weeks, the enzymes were extracted from the dentine specimens and the collagen loss was assessed. The collagen loss varied between 0 and 40.3%. Zymography of the saliva and the dentine extract samples showed that (pro-)MMP-2 and (pro-)MMP-9 were present. The levels of active MMPs were assessed, using fluorogenic MMP-specific substrates. All but 3 of the 51 saliva samples showed MMP-1 activity ranging from 1.5 to 101.1 relative fluorescence units (RFU)/s. Forty-eight saliva samples showed gelatinolytic MMP-2/MMP-9 activity (1.7-141.1 RFU/s). MMP-1 activity was shown in all dentine extracts varying between 3.5 and 295.0 RFU/s. From the dentine extracts, 15 showed MMP-2/MMP-9 activity (0.2-13.7 RFU/s). The MMP activity from both saliva and dentine extracts did not correlate with the collagen loss. The activity of salivary cathepsin B varied from 4.8 to 42.2 arbitrary units/min. A positive correlation was found between salivary MMP activity and cathepsin B activity. This study revealed that gelatinolytic enzyme activity was present both in saliva and dentine collagen. No correlation could be observed, however, between the level of enzyme activity and the collagen loss of the dentine specimens.
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PMID:Host-derived proteinases and degradation of dentine collagen in situ. 1256 41

Degradation of type I collagen by Porphyromonas gingivalis was monitored by fluorogenic, sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), and growth assays. All three assays showed that inactivation of both the rgpA and rgpB genes was necessary to completely eliminate the capacity of P. gingivalis to cleave type I collagen. Leupeptin, an Arg-gingipain-specific protease inhibitor, almost completely inhibited collagen degradation by P. gingivalis cells whereas cathepsin B inhibitor II, a Lys-gingipain inhibitor, did not. A purified preparation of Arg-gingipains A and B hydrolyzed gelatin but did not cleave type I collagen, suggesting that the enzymes must be attached to the cell surface to exert collagenase activity. A number of substances used as adjuncts in periodontal therapy were also tested for their capacity to inhibit collagenase activity of P. gingivalis. Tetracycline, doxycycline, and chlorhexidine strongly inhibited collagenase activity.
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PMID:The collagenase activity of Porphyromonas gingivalis is due to Arg-gingipain. 1272 24

Modified lipoproteins have been suggested to modulate the expression of matrix-degrading proteases in the vascular wall. Since oxidized high density lipoprotein (HDL) has been found in atheromatous plaques and receptors for modified HDL are present on endothelial cells, we investigated the role of native and oxidized HDL3 on the expression of 35 proteases and their inhibitors in human endothelial cells using microarray analysis. Matrix metalloproteinase (MMP)-1, -2, -10, -13 and -14, tissue inhibitor of MMP (TIMP)-1, -2 and -3, cathepsin B and D, and cystatin C were expressed under basal conditions, of which MMP-10 and cystatin C expression have not been described before in endothelial cells. Native HDL3 increased MMP-1 and MMP-14 expression and decreased MMP-13 expression, whereas oxidized HDL3 increased PAI-1 and MMP-1 expression. The expression pattern was confirmed by quantitative real-time PCR. In summary, a large repertoire of matrix-degrading proteases is expressed in endothelial cells, an expression that can be modulated by native and oxidized HDL3.
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PMID:Effects of HDL3 on the expression of matrix-degrading proteases in human endothelial cells. 1279 12

Chronic rejection (CR) is the leading cause of long-term failure of transplanted kidneys. The vascular hallmark is intimal hyperplasia, accompanied by macrophage, foam cell, and T-cell infiltration. Intimal thickening results from the migration and proliferation of smooth muscle cells and increased deposits of extracellular matrix (ECM) proteins, due to release of growth factors and cytokines as well as altered ECM protein turnover. We assessed the content of fibronectin (FN) and transforming growth factor-beta1 (TGF-beta1) as well as the activities of collagenase and cathepsin B and L in renal artery walls of chronically rejected human renal allografts. We investigated renal artery samples from 8 patients with CR undergoing graftectomy, 12 patients undergoing nephrectomy, and 7 organ donors. The results were related to the DNA content of homogenates. Cathepsin B and L activities were significantly higher among those with compared with donors (P =.022). There was a trend toward higher collagenase activity in CR compared with donors and the nephrectomy group. TGF-beta1 was significantly enhanced in CR compared with donors (P =.010), and showed a trend toward higher concentrations in CR compared with the nephrectomy group. The trend was toward lower FN concentrations in CR compared with the nephrectomy group and toward higher concentrations compared with donors. Summarizing, renal CR is accompanied by enhanced proteinase activity, alterations of ECM proteins, and increased TGF-beta1 in the renal artery wall. We conclude that ECM turnover and cytokines play an important role in neointimal formation and CR pathogenesis.
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PMID:Extracellular matrix proteins, proteolytic enzymes, and TGF-beta1 in the renal arterial wall of chronically rejected renal allografts. 1452 85

In this study, we have examined the effects of specific chemical modifications of amino acid side-chains on the in vitro degradation of "native" collagen obtained from acellular matrix (ACM)-processed arteries. Two monofunctional epoxides of different size and chemistry were used to modify lysine, with or without methylglyoxal modification of arginine. Biochemical, thermomechanical, tensile mechanical, and multi-enzymatic (collagenase, cathepsin B, acetyltrypsin, and trypsin) degradation analyses were used to determine the effects of modifications.Collagen solubilization by enzymes was found to depend upon the size and chemistry of epoxides used to modify lysine residues. In general, the solubilization of native ACM collagen by collagenase, cathepsin B, trypsin, and acetyltrypsin was either unaltered or decreased after modification with glycidol. In contrast, n-butylglycidylether (n-B) treatment increased solubilization by all enzymes. Subsequent arginine modification significantly reduced collagen solubilization by acetyltrypsin for glycidol-treated ACM arteries, whereas increased collagen solubilization was observed for n-B-treated ACM arteries with all enzymes. Gel chromatographic analyses of collagen fragments solubilized by trypsin revealed that both the amount and sites of cleavage were altered after lysine and arginine modification. The ability to modulate the enzymatic degradation of tissue-derived materials as demonstrated in this study may facilitate the design of novel engineering scaffolds for tissue regeneration or collagen-based drug delivery systems.
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PMID:Modulation of collagen proteolysis by chemical modification of amino acid side-chains in acellularized arteries. 1474 23

Tumor necrosis factor-alpha (TNF-alpha) is a major mediator of inflammatory response in many diseases. It inhibits bone formation and stimulates bone resorption. To determine the molecular mechanisms involved in the regulation of gene expression of osteoblast-like cells, we analyzed the effects of TNF-alpha on the human osteosarcoma cell line Saos2. We used RT-PCR to examine the effects of TNF-alpha on bone sialoprotein (BSP), core binding factor a1 (Cbfa1), osterix, alpha 1 (I) collagen, cyclooxygenase-2 (COX-2), interleukin-6 (IL-6), cathepsin B, cathepsin L and tissue inhibitors of metalloproteinase-1 (TIMP-1). TNF-alpha (10ng/ml) increased BSP, IL-6 and COX-2 mRNA levels after 3h, reaching maximal levels at 12 h. Cbfa1 mRNA levels increased after 3 h, but decreased by 24 h. Osterix, cathepsin B, cathepsin L and TIMP-1 mRNA levels did not change after stimulation with TNF-alpha. On the other hand, alpha 1 (I) collagen mRNA expression was suppressed by TNF-alpha at 24 h. Transient transfection analyses were performed using chimeric constructs of the rat BSP gene promoter linked to a luciferase reporter gene. TNF-alpha (10 ng/ml) had no effect on the promoter activities of BSP transfected into Saos2 cells. The results of gel mobility shift assays using radiolabeled double-stranded cAMP response element (CRE) and FGF2 response element (FRE) oligonucleotides in the proximal promoter of the rat BSP gene showed increased binding of nuclear proteins at 6 h. Gel mobility shift assays with radiolabelled COX-2-CRE and COX-2-NF kappa B oligonucleotides revealed an increase in the binding of nuclear proteins from TNF-alpha-stimulated Saos2 cells. These studies, therefore, showed that TNF-alpha indirectly increased BSP expression, and that it could be mediated through COX-2 and Cbfa1 expression in Saos2 osteoblast-like cells.
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PMID:Effect of TNF-alpha on human osteosarcoma cell line Saos2--TNF-alpha regulation of bone sialoprotein gene expression in Saos2 osteoblast-like cells. 1551 23

We analyzed the expression of proteases and the clinicopathologic significance in non-skull base chordoma (NSBC). By using immunohistochemical techniques, we studied the expression of matrix metalloproteinase (MMP)-1, MMP-2, MMP-9, cathepsin B (CatB), and urokinase plasminogen activator (uPA) in 29 NSBCs and compared these data with clinicopathologic parameters and the expression of cell differentiation markers. Expression of MMP-1 (P = .092), MMP-2 (P = .041), and CatB (P = .058) was associated with nuclear pleomorphism, a previously described adverse prognostic indicator. Expression of cytokeratin 8 correlated with that of MMP-1 (P = .005), MMP-2 (P = .002), and uPA (P = .032). Patients with higher MMP-2 expression had a poorer prognosis than those with lower MMP-2 expression (P = .013). We believe that NSBCs with nuclear pleomorphism or stronger epithelial character have a higher invasive ability than those without. In addition, high MMP-2 expression was an indicator of an unfavorable clinical outcome in NSBC.
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PMID:Expression of matrix metalloproteinase (MMP)-1, MMP-2, MMP-9, cathepsin B, and urokinase plasminogen activator in non-skull base chordoma. 1553 85

Poly-[N-(2-hydroxyethyl)-L-glutamine] (PHEG) and poly(ethylene glycol) (PEG)-grafted PHEG conjugates of N,N-di(2-chloroethyl)-4-phenylenediamine mustard (PDM) were synthetised. A collagenase-sensitive oligopeptide spacer was selected to link the cytotoxic agent PDM onto the polymeric carrier. First, the oligopeptide-drug conjugate, L-pro-L-leu-gly-L-pro-gly-PDM, was prepared. In a second step, the low molecular weight PDM derivative and PEG-NH(2) were coupled to a N,N-disuccinimidylcarbonate activated PHEG. Dynamic laser light scattering measurements indicated the formation of aggregates. The presence of human serum albumin had no significant effect on the diameter of the conjugates. The hydrolytic stability of the conjugates was investigated in buffer solutions. The conjugates showed an improved stability compared to the parent nitrogen mustard. The enzymatic degradation studies of the polymeric conjugates were performed in the presence of collagenase type IV (Clostridiopeptidase A; EC 3.4.24.3), cathepsin B (EC 3.4.22.1), cathepsin D (EC 3.4.23.5) and tritosomes. Only the bacterial collagenase type IV was able to cleave the spacer releasing free PDM and its peptidyl derivative, gly-L-pro-gly-PDM. The in vitro cytotoxicity of the conjugates was evaluated against HT1080 fibrosarcoma cells and MDA adenocarcinoma cells. All conjugates showed low toxicity towards these cell lines.
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PMID:Synthesis and in vitro evaluation of macromolecular antitumour derivatives based on phenylenediamine mustard. 1566 87

In this study, the effects of specific chemical modifications of amino acid side-chains on the in vitro enzyme degradation of type I collagen was studied. Two monofunctional epoxides of different size and chemistry were used to modify lysine and methylglyoxal was used to modify arginine. Lysine residues were modified using glycidol, a small hydrophilic reagent or n-butylglycidylether, a larger hydrophobic reagent. Amino acid analysis, swelling measurements, in vitro enzyme degradation analyses (using either collagenase, trypsin, acetyltrypsin, or cathepsin B), and gel chromatography were used to determine the effects of each chemical modification on purified type I collagen. Collagen solubilization by enzymes depended upon the size and chemistry of epoxides used to modify lysine residues. Modification of lysine residues by glycidol and arginine modification by methylglyoxal together significantly reduced collagen solubilization by acetyltrypsin and collagenase, whereas increased collagen solubilization was observed for all enzymes after lysine modification with n-butylglycidylether combined with arginine modification by methylglyoxal. Gel chromatographic analyses of collagen fragments solubilized by acetyltrypsin from type I collagen revealed that both the extent of solubilization and sites of cleavage were altered after lysine and arginine modification. In contrast, lysine and arginine modification only altered the amount of collagen solubilized by collagenase and had no effect on the amount collagen solubilized by cathepsin B. The ability to modulate the enzyme degradation of collagen-based materials as demonstrated in this study may facilitate the design of novel scaffolds for tissue regeneration or collagen-based drug/protein/gene delivery systems.
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PMID:The effect of chemical modification of amino acid side-chains on collagen degradation by enzymes. 1692 26


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