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)

Using immunocytochemistry and Northern blot analysis, we investigated the role of cell morphology and reorganization of the cytoskeleton in the expression of transforming growth factor-beta 1 (TGF-beta 1) in human dermal fibroblasts. Disruption of the cytoskeleton was induced by three different agents--trypsin, ethyl-eneglycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA), or cytochalasin--and was confirmed by staining with rhodamine-labeled phalloidin. Immunocytochemical staining with antibodies specific for TGF-beta 1 revealed a cell-shape-related induction of TGF-beta 1. Northern blot analysis of total RNA showed a significant increase in the expression of TGF-beta 1 mRNA as early as 4 h and peaking at 12 h after disruption of the cytoskeleton. Quantitative analysis of TGF-beta 1 mRNA expression at 4 h after treatment with trypsin, EGTA, or cytochalasin C showed increases of 2.6-, 3.3-, and 2.6-fold, respectively. Disruption of the cytoskeleton by trypsin, EGTA, or cytochalasin C increased mRNA for collagenase by 3.8-fold, 2.3-fold, or 2.5-fold, respectively. The expression of mRNA for tissue inhibitor of metalloproteinases I (TIMP-I) also showed a 3.2-fold increase by trypsin, a 3.6-fold increase by EGTA, and a 2.5-fold increase by cytochalasin C. Cell-shape-related induction of TGF-beta 1, collagenase, and TIMP-I genes appears to be selective, as the levels of mRNA for fibronectin and type I procollagen were not significantly altered. These data suggest that gene expression of TGF-beta 1, collagenase, and TIMP-I is governed by the status of the cytoskeleton microfilament organization, which may be a mechanism of gene regulation during cell division, migration, and differentiation, events fundamental to wound healing.
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PMID:Alteration in cell morphology triggers transforming growth factor-beta 1, collagenase, and tissue inhibitor of metalloproteinases-I expression in normal and hypertrophic scar fibroblasts. 752 43

The molecular basis by which transforming growth factor (TGF)-beta 1 protects certain tumor cells from tumor necrosis factor (TNF) cytotoxicity was investigated. When pretreated, with TGF-beta 1, -beta 2, and -beta 3, murine L929S fibroblasts developed resistance to TNF cytotoxicity. Time course experiments revealed that TGF-beta 1 initially induced both cellular protein-tyrosine phosphorylation and simultaneous secretion of a novel extracellular matrix TNF-resistance triggering (TRT) protein(s), which closely preceded the acquisition of TNF-resistance. TGF-beta 2 and -beta 3 also increased tyrosine phosphorylation. However, both molecules failed to stimulate TRT secretion. The increased levels of phosphorylation, particularly to 9 specific protein tyrosine kinase inhibitor-sensitive cellular proteins, appeared to alter the TNF killing pathway. TGF-beta 1-induced TRT secretion required participation of unknown serum factors. TRT adhered strongly to polystyrene plates and resisted treatment with heat (60 degrees C, 30 min), collagenase, alpha 2-macroglobulin, heparin, antibodies against TGF-beta s, and limited trypsin digestion. Notably, TRT promoted TNF-resistance via activation of tyrosine and serine/threonine kinase functions in L929S. Thus, the molecular pathway involves TGF-beta 1-mediated initiation of a rapid tyrosine phosphorylation of cellular protein substrates (which alters TNF cytotoxic pathway), and a simultaneous secretion of TRT, which in turn signals the cells to maintain the levels of phosphorylation, thereby sustaining the TNF-resistance.
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PMID:Transforming growth factor-beta 1 induction of novel extracellular matrix proteins that trigger resistance to tumor necrosis factor cytotoxicity in murine L929 fibroblasts. 753 77

We recently showed that osteogenic protein-1(OP-1), a bone morphogenetic protein member of TGF-beta superfamily, induces endochondral bone formation in vivo, and stimulates growth and differentiation of osteoblasts in rat calvarial-derived cell cultures. In the present study, we examined the effect of OP-1 on cell growth and expression of markers that are characteristic of osteoblast phenotype using the clonal rat osteosarcoma cells (ROS 17/2.8). A comparison of OP-1 and TGF-beta 1 effects on cell growth showed that, both OP-1 and TGF-beta 1 inhibited DNA synthesis up to 90 percent and 60 percent of the controls at concentrations of 10 ng/ml and 1 ng/ml, respectively, in serum-free medium. In the presence of 5% serum, TGF-beta 1 did not have any significant inhibitory effects while 40 ng OP-1/ml inhibited the DNA synthesis up to 80% of the controls. Examination of collagen synthesis showed that 40 ng OP-1/ml increased the expression of type I collagen mRNA, and thus increased collagen synthesis (4-fold), as examined by collagenase-digestible protein. Evaluation of markers that are characteristic of the osteoblast phenotype demonstrated that OP-1 stimulated cAMP production in response to PTH (10-fold at 200 ng/ml), alkaline phosphatase specific activity (ALPase) (4-fold at 80 ng/ml), and osteocalcin (OC) synthesis (4.5-fold at 40 ng/ml). Northern blot analysis revealed that OP-1 increased mRNA expression for both ALPase and OC in a dose-dependent manner. These data collectively demonstrate that OP-1 suppresses cell proliferation and stimulates the expression of markers characteristic of osteoblast phenotype in rat clonal osteoblastic osteosarcoma cells (ROS 17/2.8).
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PMID:Osteogenic protein-1 (BMP-7) inhibits cell proliferation and stimulates the expression of markers characteristic of osteoblast phenotype in rat osteosarcoma (17/2.8) cells. 773 48

Fibrochondrocytes isolated from different parts of the human knee joint meniscus were cultured, and their morphology and ability to synthesize matrix components were investigated. The mid-portion of the medial meniscus was divided into two parts (the outer one-third and the inner two-thirds), and cells were obtained for culture by pronase and collagenase digestion. The appearance of the fibrochondrocytes was different in monolayer culture from that of both articular chondrocytes and fibroblasts. However, there was no difference between the cells obtained from the two different parts of the meniscus. Although proteoglycan synthesis by cells from the inner two-thirds was higher than that by cells from the outer one-third of the meniscus, there was no difference in the collagen synthesis. Fibrochondrocytes from the meniscus were found to synthesize cartilage-like proteoglycan. Proteoglycan synthesis by meniscus cells and articular chondrocytes was stimulated by TGF-beta 1 in a dosage-dependent manner. These findings indicated that fibrochondrocytes possessed similar characteristics to articular chondrocytes in terms of proteoglycan metabolism.
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PMID:[Proteoglycan and collagen synthesis of cultured fibrochondrocytes from the human knee joint meniscus]. 780 33

The gene expressions of type I collagen and transforming growth factor-beta 1 (TGF-beta 1) were studied in lung tissue of rats exposed to air or 85% O2 for 14 days. Peak expression of type I collagen mRNA was observed by 14 days of 85% O2 exposure, at the same time as maximal immunoreactive type I collagen, which was most marked surrounding the major airways and vessels. TGF-beta 1 mRNA also significantly increased after 14, but not 4 or 6 days of 85% O2 exposure. TGF-beta 1 immunoreactivity was only detected on day 14 of 85% O2 exposure and was localized primarily to the pulmonary epithelium. As an increase in immunoreactive type I collagen was evident by day 6 of O2 exposure, the gene expressions of interstitial collagenase (MMP-1), stromelysin, and the tissue inhibitor of the metalloproteinases (TIMP) were also examined. Increased mRNA expressions of interstitial collagenase and TIMP preceded those of type I collagen and TGF-beta 1, occurring at 4-6 days of exposure to 85% O2, while there was no significant change in stromelysin mRNA. These findings are compatible with the initial O2-mediated increase in type I collagen deposition being a result of an altered proteinase/antiproteinase balance in the lung, and the subsequent more marked deposition being a response to increased TGF-beta 1 synthesis.
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PMID:Altered expression of type I collagen, TGF-beta 1, and related genes in rat lung exposed to 85% O2. 784 Feb 32

Connective tissue remodeling is essential for normal growth and development, and many diseases have long been associated with the breakdown of the collagenous matrix of bone, cartilage, and related tissues. Recent work has established that members of the family of matrix metalloproteinases (MMPs) are key enzymes in matrix degradation. They function at neutral pH and can digest synergistically all the matrix macromolecules. Biochemical and cloning studies indicate that there are three major groups, collagenases, gelatinases, and stromelysins. Naturally occurring inhibitors, TIMPs (Tissue Inhibitors of MetalloProteinases), are important controlling factors in the actions of MMPs, and tissue destruction in disease processes often correlates with an imbalance of MMPs over TIMPs. The major inhibitor is TIMP-1 (or TIMP), a 30-kDa glycoprotein that is synthesized by most cells. The expression of MMPs and TIMPs by cells is regulated by many cytokines (particularly interleukin-1, IL-1), growth factors, and hormones, some of which are specific to cell type and others that are ubiquitous (e.g., transforming growth factor beta, TGF-beta). One way in which pathogenic organisms might mediate tissue degradation in periodontal diseases is through the ability of cell wall antigens to stimulate cytokine production by circulating mononuclear cells. These would then induce MMP synthesis by resident gingival cells, thereby initiating degradative events. Direct in vivo evidence for the source of collagenase and other MMPs in periodontal tissues is limited. By using specific polyclonal antibodies and indirect immunofluorescence, we could demonstrate the presence of collagenase, stromelysin-1, gelatinase A, and TIMP in human gingival biopsy specimens.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Connective tissue degradation in health and periodontal disease and the roles of matrix metalloproteinases and their natural inhibitors. 786 92

The cellular redox state is altered in a number of pathological conditions, including various forms of glomerular injury and diabetes. For example, glucose, via the pentose phosphate pathway generates NADPH, which maintains glutathione (GSH) (part of a major intracellular reducing system) in its reduced state. GSH in turn influences the activity of transcription factors on gene expression. We therefore examined whether changes in cellular GSH influence total collagen synthesis and mRNA levels for collagen I, collagen IV and TGF-beta in SV-40 transformed mouse mesangial cells (MC) maintained in either 5 or 25 mM glucose media. Total intracellular GSH was increased by N-acetylcysteine (NAC; 10 mM) or decreased with the GSH synthesis inhibitor buthionine sulfoximine (BSO; 0.2 mM) in MC. NAC increased 3H-proline incorporation into collagenase-sensitive protein while BSO decreased it under both glucose conditions. The presence of BSO did not reverse the increased collagen synthesis seen in the NAC stimulated cells. Northern blot analysis showed increased mRNA levels for collagen I, collagen IV and TGF-beta in cells grown in high glucose (25 mM). NAC increased the mRNA for all three compounds while BSO alone had no effect on these mRNA levels. However, BSO reversed the increased mRNA levels for collagen I, IV and TGF-beta seen in the presence of NAC. These findings suggest that the cellular redox state may influence gene transcription in MC, and may have implications in explaining injury-associated alterations of mesangial matrix generation.
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PMID:Intracellular glutathione influences collagen generation by mesangial cells. 796 50

Altered regulation of metalloproteinases may play a role in a variety of pathologic conditions including cancer. Previous studies have demonstrated transforming growth factor-beta 1 (TGF-beta 1)-mediated stimulation of expression and activation, and phorbol ester-mediated inhibition of matrix metalloproteinase (MMP)-2 (72-kDa type IV collagenase/gelatinase A), indicating a role for transmembrane signal transduction in MMP-2 regulation. We now describe a role for calcium mobilization in the regulation of MMP-2 expression. Receptor-operated calcium influx has been shown to be inhibited by a novel synthetic inhibitor, carboxy amido-triazole (CAI). Incubation of A2058 human melanoma, HT-1080 human fibrosarcoma, and OVCAR3 human ovarian cancer cells with CAI (0-10 microM) resulted in a dose-dependent reduction in MMP-2 latent and activated species activity by zymogram analysis of conditioned medium. This reduction is not due to direct inhibition of the enzyme by CAI or CAI-induced MMP-2 degradation. Decreased quantity of secreted MMP-2 protein in CAI-treated cells was shown by immunoblot and pulse-chase analysis of newly synthesized MMP-2. Cell coincubation with CAI (2 microM) and TGF-beta 1 (5 ng/ml) caused a decrease in the overall amount of latent and activated MMP-2 by zymogram and immunoblot analysis and showed that CAI inhibited TGF-beta 1 stimulation of MMP-2 production at the level of RNA expression. This was confirmed by Northern analysis of A2058 cells treated with CAI (2 microM) for 24 and 48 h and demonstrated a 55% reduction in message for MMP-2 and a 61% reduction in message for MMP-1, 54-kDa interstitial collagenase. Specificity for CAI action was demonstrated by equivalent MMP-2 inhibitory activity from analogs of CAI that retained the ability to inhibit calcium influx and by lack of inhibition by exposure to inactive CAI analogs that could not inhibit calcium influx. As an independent verification of specificity, a marked reduction in MMP-2 gelatinase activity by zymogram was shown after treatment of A2058 cells with SK&F 96365, an unrelated inhibitor of receptor-operated calcium influx. These results suggest a role for calcium-mediated signal transduction in the expression of metalloproteinases.
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PMID:Calcium influx modulates expression of matrix metalloproteinase-2 (72-kDa type IV collagenase, gelatinase A). 806 86

The triad of inflammation, immunoproliferation and synovial hyperplasia is recognized in the pathogenesis of rheumatoid arthritis, however, the sequence of events remains as highly controversial as ever. The "RA pyramid" was established on the assumption that inflammation is at the top with the destructive processes as sequelae. The moderate successes achieved by conservative therapy with regard to long-term outcome cast doubt on this hypothesis. Inhibitors of prostaglandin synthesis have not been and are not disease modifying. Do substances which influence the endothelial adhesion molecules or leucocyte adhesion receptors (leumedines) promise to be more successful? Do the empirically developed disease modifying antirheumatic drugs (Gold parenteral, MTX) have to be administered earlier? Unfortunately, there is a need for a differential diagnosis which is prognostically valid with regard to the dynamics and aggressiveness of rheumatoid arthritis. Moreover, a pharmacological basis for optimally founded combination strategies is also lacking. Presently, the emphasis of research is directed at the regulation of dysfunctional immune systems. Immunosuppressives (cyclosporin A), cytokine antagonists, receptor antagonists and soluble cytokine receptors (IL-1, IL-6, TNF-alpha), antibodies against lymphocyte subgroups (CD4, CD7) or against cytokines and their receptors are part of the arsenal for the medium term. Too little is still known about the role of protective cytokines (TGF-beta, IL-4, gamma-INF). Currently, however, it is prognosticated that these targeted therapies will only succeed in RA subgroups or only in intelligent combinations. More attractive alternative are strategic therapy modalities which intervene very early in the pathological process, such as the modulation of antigen presentation (MHC blocking peptides, T-cell receptor antagonists, T-cell vaccination) or the induction of tolerance against autoantigens through the oral administration of antigens (collagen II, HSP's, OM-8980). If the center of the pathological process, however, is found in the synovial proliferation of tumor-like cell clusters, then there are only a few years at the beginning of the disease when there is a real chance to impede destruction. In this case, aggressive induction therapy can be the only key to success. In the future, specifically active cytostatics (inhibitors of angiogenesis) will have to be developed and clinical trials conducted on adjuvant therapies with substances which strengthen bone and cartilage, making them more resistant to aggressive cell clusters (bisphosphonates, calcitonins, metalloproteinase- or collagenase-inhibitors).
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PMID:[Present and future therapeutic strategies in rheumatoid arthritis]. 814 31

Dermal equivalents (DEs), fabricated by seeding fibroblasts into a collagen lattice, may be used as in vitro models for studying wounding and the remodelling processes observed in vivo. We investigated fibroblast responses to a wound stimulus in vitro by making small wounds in DEs. We found that, following wounding, fibroblasts appeared to migrate towards and into the wound defect and appeared to initiate the closure of the wound by bringing together the cut collagen surfaces over a period of 5-11 days. Fibroblast movement into the wound defects was significantly stimulated in the presence of EGF and PDGF (2.8- and 3.5-fold respectively) but not TGF-beta. Cell proliferation in wounded DEs was up to 21% greater than in non-wounded DEs and cell numbers were stimulated further by the addition of TGF-beta, EGF and PDGF (1.5-, 1.7- and 1.8-fold respectively). Wounded DEs also displayed a 2.1-fold increase in latent collagenase production followed by a 1.3-fold increase in active collagenase levels compared to non-wounded DEs. Staining actin fibers within fibroblasts using rhodamine-phalloidin showed that fibroblasts in DEs were under tension, but that this tension was lost upon wounding. Subsequently the stress fibers reappeared concomitantly with the observed "healing" process. Additionally a continuous cell-cell actin cable purse-string developed around the entire wound edge which may be involved in wound closure. The findings suggest that the wounded dermal equivalent offers a valuable model for studying wound healing in vitro.
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PMID:The wounded dermal equivalent offers a simplified model for studying wound repair in vitro. 816 47


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