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)

Keloids are characterized by an overabundant deposition of collagen, and they recur frequently following excision. Fibroblasts isolated from keloid tissue and maintained in cell culture continue to express an increased capacity to produce collagen. In an effort to define the mechanisms responsible for keloid formation, the potential of exogenous transforming growth factor beta 1 (TGF-beta 1) to differentially affect DNA synthesis and collagen expression in cultured human fibroblasts derived from keloid or normal dermis was investigated. In this study, TGF-beta 1 at a concentration of 5.0 ng/ml was found to stimulate DNA synthesis of keloid-derived fibroblasts to a greater extent than fibroblasts derived from normal dermis. With a microassay to measure levels of collagenase-digestible radiolabeled proteins, TGF-beta 1 was found to elicit a greater increase in absolute collagen synthesis in keloid-derived fibroblasts compared with fibroblasts derived from normal dermis. Examination of tRNA(pro) pool-specific activities indicated that these observed differences in rates of collagen synthesis were not the result of unequal rates of proline transport or pool size. Likewise, TGF-beta 1 did not alter the uptake of vitamin C, an essential cofactor and mediator needed for maximal collagen expression. The increase in collagen synthesis by keloid-derived fibroblasts treated with TGF-beta 1 was accompanied by a corresponding increase in procollagen type I mRNA levels, indicating that the differential response of keloid and normal dermal fibroblasts to this growth factor is occurring primarily at a pretranslational level. These results suggest a unique sensitivity of keloid fibroblasts to TGF-beta 1 and thus a possible role for this mediator in keloid pathogenesis.
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PMID:The effect of TGF-beta on keloid fibroblast proliferation and collagen synthesis. 882 22

End organ ischemia, fragmentation of elastic membranes, and aneurysm formation in patients with giant cell vasculitis results from an inflammation destroying the mural layers of large and medium sized arteries. Although the inflammatory infiltrate extends through all layers of the affected blood vessel, the most pronounced changes involve the intima and the internal elastic lamina. Analysis of the functional profile of tissue infiltrating CD68+ cells demonstrates that different subsets of macrophages can be distinguished. TGFbeta1-expressing CD68+ cells coproduce IL-1beta and IL-6, are negative for inducible nitric oxide synthase (iNOS), and exhibit a strong preference for localization in the adventitia. The adventitial homing of TGFbeta1+ CD68+ cells places them in the vicinity of IFN-gamma secreting CD4+ T cells which also accumulate in the exterior layer of the artery. Conversely, iNOS expressing CD68+ cells are negative for TGFbeta and are almost exclusively found in the intimal layer of the inflamed artery. The intimal-medial junction is the preferred site for 72-kD collagenase expressing CD68+ cells. Thus, TGFbeta1-producing macrophages colocalize with activated CD4+ T cells and home to an area of inflammation which is distant from the site of tissue damage but critical in regulating cellular influx, suggesting that TGFbeta1 functions as a proinflammatory mediator in this disease. iNOS- and 72-kD collagenase-producing macrophages accumulate at the center of pathology implying a role of these products in tissue destruction. These data indicate that the microenvironment controls the topographical arrangement as well as the functional commitment of macrophages.
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PMID:Correlation of the topographical arrangement and the functional pattern of tissue-infiltrating macrophages in giant cell arteritis. 883 14

Streptozotocin-treated C57B1/SJL mice developed glomerular hypertrophy and light microscopic lesions mimicking human diabetic glomerulosclerosis. In contrast, there were no glomerular hypertrophy and lesions in diabetic mice transgenic (TG) for a mutated growth hormone (bGH-G119K) that competes with native endogenous GH and results in dwarfism. We examined the molecular events underlying these findings. The non-transgenic (non-TG) diabetic mouse glomeruli had an increase in mRNA coding for alpha 1IV collagen, laminin B1, TGF-beta 1, 72 kDa collagenase, and TIMP-3. In contrast, glomerular type IV collagen and laminin B1 mRNA levels were normal in diabetic TG dwarf mice. However, the 72 kDa gelatinase, TIMP-3, and TGF-beta 1 mRNAs were elevated in the diabetic dwarfs. Type IV collagen and laminin accumulated in the glomeruli of diabetic non-TG, but not of diabetic dwarf mice, by immunofluorescence microscopy, confirming the mRNA data. GH binding protein mRNA levels were comparable in glomeruli from dwarf and non-TG mice, both diabetic and non-diabetic. We did not detect GH receptor mRNA in glomeruli. These data suggest that diabetic glomerulosclerosis is associated with an increase in type IV collagen and laminin synthesis, and that these changes do not occur in mice transgenic for bGH119K, a functional antagonist of GH. The increase of 72 kDa gelatinase, TIMP-3 and TGF-beta 1 mRNAs, independent of GH, suggested that these changes induced by hyperglycemia were not sufficient for the induction of glomerulosclerosis.
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PMID:Inhibition of diabetic nephropathy by a GH antagonist: a molecular analysis. 884 Feb 79

A tissue culture system for rat prostatic epithelial cells was developed, and the effect of epidermal growth factor (EGF), transforming growth factor alpha (TGF-alpha), and transforming growth factor beta 1 (TGF-beta 1) on these cells was evaluated. The primary culture was prepared by DNAse/collagenase dissociation of minced ventral prostates. Cells were initially plated in RPMI-1640 medium containing 10% fetal bovine serum to allow the preferential attachment of stromal cells. Twenty-four hours later, the unattached epithelial cells were replated in WAJC-404 medium supplemented with insulin (5 micrograms/ml), transferrin (5 micrograms/ml), and selenious acid (5 ng/ml). Bovine pituitary extract (BPE) (30 micrograms/ml), EGF (10 ng/ml), and TGF-beta 1 (0, 0.1, and 1.0 ng/ml) were added either alone or in combination according to experimental requirements. The rate of cell proliferation was assessed by counting the total cell number and by [3H]thymidine incorporation. Prostatic epithelial cells exhibited a bell-shaped growth curve in a span of 7-8 days, with a growth peak at day 3 or 4 of culture. Treatment of cells with EGF or TGF-alpha resulted in a concentration-dependent increase in cell growth, whereas addition of TGF-beta 1 into the culture resulted in an inhibition of cell proliferation that could be reversed with increasing concentrations of EGF. Cell death was assessed using the terminal deoxynucleotidyl transferase (TdT)-mediated immunoperoxidase-digoxigenin nick end labeling technique and the trypan blue exclusion test. Epithelial cells cultured in media containing EGF had the lowest incidence of cell death. Cells cultured in the absence of EGF demonstrated a marked increase in cells undergoing cell death. The addition of TGF-beta 1 into the EGF-depleted medium caused a further increase of cell death. These results indicated that cell proliferation and cell death in rat prostatic epithelial cells in culture could be modulated by EGF and TGF-beta 1. The former stimulated cell proliferation and prevented cell death, whereas the latter inhibited proliferation in the presence or absence of EGF and induced cell death.
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PMID:Effect of TGF-beta 1, TGF-alpha, and EGF on cell proliferation and cell death in rat ventral prostatic epithelial cells in culture. 886 96

Signalling via MHC class II in human fibroblast-like synoviocytes selectively induces interstitial collagenase gene expression over its natural inhibitor, the tissue inhibitor of metalloproteinase (TIMP), through a prostaglandin E2 (PGE2)-dependent pathway involving cyclooxygenase-2 (COX-2) and cytosolic phospholipase A2 (cPLA2). In the present study, we investigated the effect of three different agents the T-cell-derived cytokine IL-4, transforming growth factor beta 1 (TGF-beta 1), and dexamethasone (DXS) on this response. Our results indicate that treatment of superantigen-stimulated synoviocytes with DXS or IL-4 inhibited collagenase gene expression without affecting TIMP gene expression. In contrast, treatment of superantigen-stimulated synoviocytes with TGF-beta 1 resulted in an inhibition of collagenase induction and an increase in TIMP gene expression. IL-4, TGF-beta 1, and DXS abolished PGE2 production and the expression of COX-2 and cPLA2 but failed to affect the constitutive expression of COX-1 and secreted PLA2. Moreover, all agents abolished protein production and phosphorylation of COX-2 and cPLA2, respectively. The inhibitory effect of the three agents on collagenase gene expression was partially reversed by exogenous PGE2, which confirms that major histocompatibility complex class II-induced collagenase gene expression is regulated through a PGE2-mediated pathway. These data highlight a mode of action of a classical anti-inflammatory agent (DXS) and of two cytokines with recognized anti-inflammatory characters (IL-4 and TGF-beta 1) on a major histocompatibility complex class II-induced response and support the involvement of COX-2 and cPLA2 in major histocompatibility complex class II-induced interstitial collagenase production in human fibroblast-like synoviocytes.
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PMID:Interleukin-4, transforming growth factor beta 1, and dexamethasone inhibit superantigen-induced prostaglandin E2-dependent collagenase gene expression through their action on cyclooxygenase-2 and cytosolic phospholipase A2. 887 84

In culture, nontransformed human diploid fibroblasts divide a limited number of times, resulting in a nonproliferating senescent cell culture which exhibits an altered pattern of gene expression. Previously we reported that an early event in the process of replicative senescence was an increase in the synthesis of two connective tissue degrading metalloproteinases, collagenase and stromelysin, and a decrease in the synthesis of the physiological inhibitor of those enzymes, tissue inhibitor of metalloproteinases-1 (TIMP-1). The cytokine TGF-beta1 is known to regulate the expression of each of these three genes and to be synthesized and secreted by cultured human fibroblasts. This suggested the hypothesis that the age-specific modulation of collagenase, stromelysin, and TIMP-1 expression is the result of a change in TGF-beta1 activity during replicative senescence. To test this hypothesis, the responses of early, mid, and late passage (presenescent) fibroblast cell cultures to a TGF-beta neutralizing antibody were evaluated. In early passage cell cultures, exposure to TGF-beta neutralizing antibody resulted in a significant increase in the expression of collagenase and stromelysin and decreased TIMP-1 expression. The antibody did not affect expression of either of those genes by late passage cell cultures, although late passage cultures did respond to added TGF-beta1. Quantification of the levels of active TGF-beta, using a growth inhibition assay, indicates that the level of active TGF-beta1 is decreased during replicative senescence, supporting the conclusion that the modulation of collagenase, stromelysin, and TIMP-1 expression results from diminished TGF-beta activity.
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PMID:Endogenous TGF-beta activity is modified during cellular aging: effects on metalloproteinase and TIMP-1 expression. 891 20

The cellular events causing pathological extracellular matrix (ECM) accumulation in vivo are not well understood. Prolonged serial passage of several cell types in culture leads to increased production of extracellular matrix (ECM) proteins, but the mechanism for these putative fibrotic changes is not known. Here, human fetal glomerular mesangial cells were subjected to serial passage (P) in culture and the expression of ECM proteins, proteases and protease inhibitors was comprehensively evaluated. From P11 through P14, a series of phenotypic changes occurred. Steady-state expression of mRNA for alpha 1 chains of type III and type IV (but not type I) collagen, and for laminin beta 1 and gamma 1, increased 2- to 8-fold, while expression of mRNA for interstitial collagenase (MMP-1) and gelatinase A (MMP-2) virtually ceased. Expression of tissue-type plasminogen activator (tPA) mRNA also decreased markedly. Expression of mRNA for the tissue inhibitor of metalloproteinases (TIMP)-1, and of the smaller of two mRNA species for the PA inhibitor PAI-1, ceased by P14. There was a switch in expression of the two species of TIMP-2 mRNA: whereas the ratio of signal intensity comparing the 3.5 kb mRNA species to the 1.0 kb species was 5:1 up to P11, it was reversed (1:5) at P14 and later. Serial passage also led to changes in protein expression, with increased type IV collagen and laminin, but decreased interstitial collagenase and gelatinase A. The cells showed a progressive increase in staining for type IV collagen. These findings define the appearance of a matrix-accumulating phenotype in later-passage mesangial cells. Matrix expansion in vivo has been associated with increased transforming growth factor (TGF)-beta synthesis; the cells were found to show at least 5-fold increased expression of TGF-beta 1 mRNA from P8 to P16. However, treatment of P9 or P10 cells with graded doses of TGF-beta 1 increased expression of both collagen IV and gelatinase A mRNA and did not alter the ratio of signal intensity for TIMP-2 mRNA species. Thus, assumption of a matrix-accumulating phenotype by these cultured fetal glomerular mesangial cells is not accelerated by exogenous TGF-beta. These data describe an in vitro model of mesangial cell matrix turnover in which matrix accumulation could result from a concerted increase in ECM synthesis and decrease in ECM degradation.
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PMID:Increased expression of extracellular matrix proteins and decreased expression of matrix proteases after serial passage of glomerular mesangial cells. 892 13

Pulmonary fibrosis is the common end stage of a number of pneumopathies. In this study, we examined the ability of the human cytokine, relaxin, to block extracellular matrix deposition by human lung fibroblasts in vitro, and to inhibit lung fibrosis in a bleomycin-induced murine model. In vitro, relaxin (1-100 ng/ml) inhibited the transforming growth factor-beta-mediated over-expression of interstitial collagen types I and III by human lung fibroblasts by up to 45% in a dose-dependent manner. Relaxin did not affect basal levels of collagen expression in the absence of TGF-beta-induced stimulation. Relaxin also blocked transforming growth factor-beta-induced upregulation of fibronectin by 80% at the highest relaxin dose tested (100 ng/ml). The expression of matrix metalloproteinase-1, or procollagenase, was stimulated in a biphasic, dose-dependent manner by relaxin. In vivo, relaxin, at a steady state circulating concentration of approximately 50 ng/ml, inhibited bleomycin-mediated alveolar thickening compared with the vehicle only control group (P < 0.05). Relaxin also restored bleomycin-induced collagen accumulation, as measured by lung hydroxyproline content, to normal levels (P < 0.05). In summary, relaxin induced a matrix degradative phenotype in human lung fibroblasts in vitro and inhibited bleomycin-induced fibrosis in a murine model in vivo. These data indicate that relaxin may be efficacious in the treatment of pathologies characterized by lung fibrosis.
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PMID:Relaxin induces an extracellular matrix-degrading phenotype in human lung fibroblasts in vitro and inhibits lung fibrosis in a murine model in vivo. 898 19

Hyperglycemia is a principal characteristic of diabetes, and has an influence on many cellular functions. In order to investigate whether the intracellular signaling pathways inducing proliferation, hypertrophy and matrix synthesis of mesangial cells are altered in a diabetic environment, we evaluated the effects of a high concentration of extracellular glucose(25 mM; 450 mg/dl) on [3H]thymidine uptake, hypertrophy, and [3H]proline incorporation into a collagenase-sensitive protein, induced by angiotensin II(Ang II) or transforming growth factor(TGF)-beta, in cultured rat mesangial cells. The exposure to a high glucose concentration for 7 days significantly inhibited Ang II(10(-6) M)-induced [3H]thymidine uptake, compared to normal glucose concentration (5 mM)(M +/- SD., 1050 +/- 100 cpm/well vs 550 +/- 97, p < 0.05), and markedly prevented the inhibition of [3H]thymidine uptake by TGF-beta(1 ng/ml)(132 +/- 10 vs 340 +/- 67, p < 0.05). The administration of H-7(50 microM), a protein kinase C(PKC) inhibitor, did not reverse these effects of high glucose on [3H]thymidine uptake. On flow cytometric analysis of cell size, the mean cell size was significantly greater for the cells exposed to high glucose or treated with Ang II or TGF-beta, compared to that for the untreated cells. But the addition of Ang II or TGF-beta to the cells exposed to high glucose did not show further enlargement in size. The exposure to high glucose and the treatment with Ang II or TGF-beta significantly increased collagen synthesis, measured by [3H]proline incorporation. The Ang II -or TGF-beta-induced increase of [3H]proline incorporation did not show changes under high glucose culture condition, compared to normal glucose concentration(Ang II, 27880 +/- 3560 cpm vs 26978 +/- 2284, TGF-beta, 26559 +/- 3700 vs 25800 +/- 1660, p > 0.05). In conclusion, although the signaling pathway for DNA synthesis by Ang II or TGF-beta are influenced, possibly mediated by PKC-independent mechanism(s), the pathway inducing hypertrophy or collagen synthesis by both agents appears to be unchanged under the high extracellular glucose concentration in cultured rat mesangial cells.
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PMID:The effects of high glucose concentration on angiotensin II- or transforming growth factor-beta-induced DNA synthesis, hypertrophy and collagen synthesis in cultured rat mesangial cells. 899 62

Human collagenase-3 (MMP13) is a recently identified member of the matrix metalloproteinase (MMP) family that is expressed in breast carcinomas and in articular cartilage from arthritic patients. In this work we have isolated and characterized genomic clones coding for human collagenase-3. This gene is composed of 10 exons and 9 introns and spans over 12.5 kb. The overall organization of the collagenase-3 gene is similar to that of other MMP genes clustered at chromosome 11q22, including fibroblast collagenase (MMP-1), matrilysin (MMP-7), and macrophage metalloelastase (MMP-12), but is more distantly related to genes coding for stromelysin-3 (MMP-11), gelatinase-A (MMP-2), and gelatinase-B (MMP-9), which map outside of this gene cluster. Nucleotide sequence analysis of about 1 kb of the 5'-flanking region of the collagenase-3 gene revealed the presence of a TATA box, an AP-1 motif, a PEA-3 consensus sequence, an osteoblast specific element (OSE-2), and a TGF-beta inhibitory element. Transient transfection experiments in HeLa and COS-1 cells with chloramphenicol acetyltransferase (CAT)-containing constructs showed that the AP-1 site is functional and responsible for the observed inducibility of the reporter gene by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA). However, and in contrast to other MMP genes, no significative synergistic effect on CAT activity between the AP-1 and PEA-3 elements found in the collagenase-3 gene promoter was found. DNA binding analysis with nuclear extracts from HeLa cells revealed the formation of specific complexes between collagenase-3 promoter sequences containing the AP-1 site and nuclear proteins. The presence of this AP-1 functional site, which is able to confer responsiveness to a variety of tumor promoters and oncogene products, amy contribute to explaining the high-level expression of collagenase-3 in breast carcinomas and degenerative joint diseases.
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PMID:Structural analysis and promoter characterization of the human collagenase-3 gene (MMP13). 911 88


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