Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.23 (MMP)
 4,246 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The present study was designed to assess whether expression of mRNA for extracellular matrix (ECM) components, metalloproteinases (MMP) and tissue inhibitor of metalloproteinases (TIMP) in glomeruli is affected by a low protein diet during the course of focal glomerulosclerosis (FGS). Puromycin aminonucleoside (PAN) was injected intraperitoneally in rats and the right kidney was removed on day 22. Nephrotic rats received successive intraperitoneal injections of PAN on days 27, 34, and 41. Control rats were subjected to a nephrectomy or a sham operation on day 22. Animals were divided into six groups. In group 1, the PAN-injected rats were fed a standard diet containing 22% protein. In group 2, the PAN-injected rats were fed a low protein diet containing 6% protein, starting on the same day as the first PAN injection. In group 3, the nephrectomized rats without PAN were fed a standard diet. In group 4, the nephrectomized rats without PAN were fed a low protein diet for the same period. In group 5, the sham operated rats were fed a standard diet. In group 6, the sham operated rats were fed a low protein diet for the same period. Rats were sacrificed on days 0, 60 or 80 after the initial PAN or saline injection. The percentage of sclerotic glomeruli in group 1 rats increased markedly with time, reaching 77% on day 80. The mRNA levels encoding for alpha 1(I), alpha 1(III), alpha 1(IV) collagen chains, laminin B1 and B2 chains, heparan sulfate proteoglycan (HSPG), MMP-2, TIMP-1 and TIMP-2 increased significantly as glomerulosclerosis progressed, whereas MMP-1 and MMP-3 mRNA levels were unchanged, and no MMP-9 mRNA was detected throughout the experiments. In group 2, the low protein diet reduced the prevalence of glomerulosclerosis and attenuated the increased mRNA expression for ECM components, MMP-2, TIMP-1 and TIMP-2 in FGS glomeruli. In groups 3 through 6, mRNA levels for ECM components decreased with age, whereas those for MMPs and TIMPs changed little throughout the experiments. Immunofluorescence studies revealed the accumulation of types I, III and IV collagens, laminin, and HSPG in the sclerotic area and low protein diet attenuated the accumulation of these proteins. These data suggest that glomerulosclerosis may result from an imbalance among ECM components, MMPs and TIMPs and that a low protein diet attenuates the otherwise increased levels of mRNA for ECM components, MMP-2, TIMP-1 and TIMP-2 in glomerulosclerosis.
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PMID:Low protein diet blunts the rise in glomerular gene expression in focal glomerulosclerosis. 793 7

The extra-cellular matrix (ECM) related antigens, type IV collagen, laminin, M(r) 68,000 laminin receptor (LR), M(r) 72,000 type IV collagenase (MMP-2), its inhibitor TIMP-2, and alpha 2-macroglobulin expression have been immunohistochemically investigated in 100 cases of human gastric carcinoma with a 5-yr follow up. Basement membranes were inversely related to tumoral differentiation. At the early intramucosal stage of both intestinal and diffuse histological types, TIMP-2 was expressed by the majority of tumor cells (60/63%), whereas MMP-2+ and LR+ cells were in the minority (24/19%, 23/0%, respectively). At the early submucosal stage, TIMP-2+ cells moderately decreased in both histological types (49/49%), whereas a consistently higher number of both MMP-2+ and LR+ cells were detected only in the diffuse carcinomas (72%). In the advanced stage, the expression of TIMP-2 further declined (22/24%), although the other two antigens increased or maintained high levels of expression. AMG+ cells never exceeded 10% in either histological type at any stage. In the liver metastases, both MMP-2+ and LR+ cells were more numerous than in the primary tumor (P < 0.002 and P < 0.01). Patients who died from their primary tumor had higher percentages of LR+, MMP-2+, and AMG+ cells and lower percentages of TIMP-2+ cells with respect to survivors. We believe evaluation of ECM-related antigens, and especially TIMP-2, may help determine a confident prognosis for gastric cancer.
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PMID:Prognosis of gastric carcinoma revealed by interactions between tumor cells and basement membrane. 800 47

Matrix metalloproteinases (MMPs) play a role in tissue remodelling and angiogenesis. We have investigated the expression and regulation of MMP-1 (interstitial collagenase), MMP-2 (gelatinase A), MMP-3 (stromelysin 1), MMP-7 (matrilysin), MMP-9 (gelatinase B) and their inhibitors TIMP-1 and TIMP-2 in human umbilical vein, femoral vein and microvascular endothelial cells, and compared these data with those obtained with human synovial fibroblasts. Non-stimulated vein endothelial cells expressed the mRNAs for MMP-1, MMP-2, TIMP-1 and TIMP-2. MMP-3 mRNA and protein were undetectable or only weakly expressed, but could be stimulated by the inflammatory mediator tumour necrosis factor alpha (TNF alpha). The expression of MMP-3 and MMP-1 was further enhanced by phorbol 12-myristate 13-acetate (PMA). Phorbol ester also induced TIMP-1 and MMP-9, the expression of the latter being further enhanced by TNF alpha or interleukin 1 alpha (IL-1 alpha). Similar stimulatory effects were observed in microvascular endothelial cells. Hence the inflammatory mediator TNF alpha induces/enhances the production of several matrix metalloproteinases in human endothelial cells. On the other hand, MMP-2 and TIMP-2 were not affected or were affected in a variable way by TNF alpha and/or phorbol ester, suggesting a dissimilar regulation of these proteins. The cyclic AMP-enhancing agent forskolin affected the production of MMPs in a cell-type-specific way. In human vein endothelial cells it enhanced the PMA-mediated induction of MMP-9, whereas it suppressed this induction in human microvascular endothelial cells and in synovial fibroblasts. On the other hand, forskolin suppressed the PMA-mediated induction of MMP-1 and MMP-3 in synovial fibroblasts, while it enhanced or did not affect this induction in various types of human endothelial cells. These observations may have implications for future pharmacological intervention in angiogenesis.
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PMID:Regulation of matrix metalloproteinase expression in human vein and microvascular endothelial cells. Effects of tumour necrosis factor alpha, interleukin 1 and phorbol ester. 828 80

Multiple forms of metalloproteinase inhibitors were found in the serum-free conditioned medium of the EJ-1 human bladder carcinoma cell line by reverse zymography assay with gelatinase A as the indicator enzyme. Two novel forms of inhibitor with apparent molecular masses of 18 and 22 kDa on nonreducing SDS-polyacrylamide gel electrophoresis (PAGE), together with tissue inhibitor of metalloproteinases (TIMP) and TIMP-2, were purified from the conditioned medium by a series of chromatographic steps. Structural analysis showed that the 18-kDa inhibitor is a two-chain form of TIMP-2 (tc-TIMP-2) produced by proteolytic processing, and the 22-kDa inhibitor may be a partially glycosylated form of TIMP. The purified tc-TIMP-2 was separated into a 17-kDa peptide and a small peptide of about 2.5 kDa by reducing SDS-PAGE and into four isoforms with pI 7.6, 7.3, 7.2, and 6.8 by isoelectric focusing. tc-TIMP-2 has essentially the same inhibitory activity as TIMP-2 toward gelatinase A, collagenase, stromelysin, and matrilysin. Unlike TIMP-2, however, tc-TIMP-2 does not bind to the latent precursor fo gelatinase A. Similar two-chain forms of TIMP-2 were produced by its partial digestion with trypsin or less effectively with plasmin. These results suggest that proteolytic processing of TIMP-2 plays a role in the regulation of gelatinase A activity in the extracellular matrix.
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PMID:Purification and characterization of a two-chain form of tissue inhibitor of metalloproteinases (TIMP) type 2 and a low molecular weight TIMP-like protein. 831 98

We examined the anti-invasive activity of ursolic acid (UA) on the highly metastatic HT1080 human fibrosarcoma cell line. UA reduced tumor cell invasion through a reconstituted basement membrane in a transwell chamber. A significant down-regulation of matrix metalloproteinase-9 [MMP-9; Mr 92,000 gelatinase/type IV collagenase (gelatinase B)] by UA was detected by Northern blot analysis. However, MMP-2 [Mr 72,000 gelatinase/type IV collagenase (gelatinase A)] and membrane-type MMP were constantly expressed, and the expression of tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2 also was not changed after 3 and 6 days of treatment with UA. Quantitative gelatin-based zymography confirmed a markedly reduced expression of MMP-9 but not MMP-2 after treatment with UA. To confirm the UA-induced down-regulation of MMP-9 expression, we constructed a secreted alkaline phosphatase (SEAP) reporter vector including MMP-9 promoter. After transfection of MMP-9/SEAP reporter vector into HT1080 cells, reduced SEAP activity was detected after treatment with UA. These results suggest that down-regulation of MMP-9 contributes to the anti-invasive activity of UA in HT1080 cells.
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PMID:Anti-invasive activity of ursolic acid correlates with the reduced expression of matrix metalloproteinase-9 (MMP-9) in HT1080 human fibrosarcoma cells. 862 99

92-kDa type IV collagenase/gelatinase (matrix metalloproteinase-9; MMP-9; gelatinase B) expression and secretion has been shown to correlate with the invasive and metastatic potential of various malignant cells. MMP activity is tightly controlled by specific tissue inhibitors of metalloproteinases (TIMPs). We found the leukemic cell line HL-60 constitutively to release a 94-kDa gelatinase which we identified as MMP-9 shortened by nine amino acids at its N-terminal end. An additional gelatinolytic activity was present in small amounts and identified as a 63-kDa fragment of MMP-9 generated by autocatalytical processing. Both enzymes were identical regarding their N-terminus, indicating C-terminal truncation for the former. Incubation of cells with phorbol ester resulted in elevated amounts of both enzymes in conditioned media and in the secretion of TIMP-1. Both gelatinases were shown to be activated by trypsin and organomercurials and to possess similar activities towards various substrates. However, the 63-kDa enzyme differed from the 94-kDa enzyme in a significantly reduced inhibition by recombinant TIMP-1 and TIMP-2. Thus, the 63-kDa fragment of MMP-9 once activated may escape the regulatory influence of its specific inhibitors and may thereby promote matrix degradation during invasion of leukemic cells.
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PMID:HL-60 leukemia cells produce an autocatalytically truncated form of matrix metalloproteinase-9 with impaired sensitivity to inhibition by tissue inhibitors of metalloproteinases. 875 73

Malignant human melanoma cells produce many matrix-degrading enzymes, including plasminogen activators and matrix metalloproteinases. These enzymes have substrate specificity for different components of ECM and most of them have been demonstrated to contribute to melanoma cell-mediated dissolution of matrices and to melanoma cell invasion. The degradation of complex matrices in vitro requires the cooperation of proteases with specificity for glycoproteins and collagens. The contribution of proteases to spontaneous melanoma metastasis was studied by overexpressing specific protease inhibitors in human melanoma cells. Overexpression of PAI-2 inhibited the spread of distant metastasis indicating a role for uPA/plasmin in melanoma invasion. Overexpression of TIMP-2, in contrast, reduced the growth rate of subcutaneous tumors, but did not inhibit metastasis, indicating that MMP activities promote melanoma growth in the skin and may not be required for metastatic dissemination. Thus, uPA and MMP activities are involved in different processes, but they both contribute to melanoma malignancy.
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PMID:Different roles for plasminogen activators and metalloproteinases in melanoma metastasis. 881 95

The studies described here examine the involvement of the fibrinolytic cascade and its endogenous inhibitors in the regulation of activity of matrix metalloproteinases and cartilage degradation related to non-inflammatory joint disease, like osteoarthritis. An interleukin-1-induced model of degradation using [35S]-labeled bovine and human articular cartilage explants was utilized. One goal of these studies was to compare the responses of bovine and human articular cartilage. Degradation was not inhibited by alpha 1-PI, PAI-1, alpha 2-macroglobulin, alpha 2-antiplasmin or TIMP-2, when IL-1 alone was added. Addition of human plasminogen to bovine explants, at concentrations found in human synovial fluid, increased degradation by three to four-fold. Under these conditions, the degradation was inhibited effectively by all of the endogenous inhibitors tested, indicating the presence of a cascade where activated chondrocytes are a source of u-PA. Plasminogen activated by u-PA gives plasmin, which is known to further activate pro-stromelysin. Stromelysin is essential for activation of collegenase. Not only TIMP, but also inhibitors at earlier steps of activation like PAI-1, alpha 2-antiplasmin, alpha 1-PI and alpha 2-macroglobulin inhibited degradation, and could provide cartilage protection in vivo. An experiment with human articular cartilage explants showed that very little or no degradation occurred when human articular cartilage explants were stimulated with interleukin-1 alone. Addition of human plasminogen (at physiologically relevant concentrations) resulted in significant degradation, which was inhibited in the same manner as in bovine explants, by inhibitors of the fibrinolytic cascade and TIMP. TIMP is much more efficient in human explants, indicating the limited participation of human plasmin in the degradation of human cartilage. Although speculative, it is possible that in vivo, cartilage degradation could be promoted not only by TIMP/MMP imbalance, but also accelerated by decreased levels of certain serpins in synovial fluid (e.g. PAIs, alpha 2-antiplasmin and alpha 1-PI).
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PMID:Plasminogen modulation of IL-1-stimulated degradation in bovine and human articular cartilage explants. The role of the endogenous inhibitors: PAI-1, alpha 2-antiplasmin, alpha 1-PI, alpha 2-macroglobulin and TIMP. 889 58

The three forms of neutrophil gelatinase B-monomer, homodimer and monomer/lipocalin complex-, were isolated from phorbolester stimulated neutrophil granulocytes by chromatography on gelatin-Sepharose and heparin-Ultrogel. On average, about 50% of the monomer/lipocalin complex was found to be complexed with TIMP-1. After activation with trypsin monomer, homodimer and monomer/lipocalin complex displayed a specific activity of about 2000 mU/mg towards the substrate N-(2,4)-dinitrophenyl-Pro-Gln-Gly-lle-Ala-Gly-Gln-D-Arg, whereas the monomer/lipocalin/TIMP-1 complex could be activated to a specific activity of only 200 mU/mg. The ternary monomer/lipocalin/TIMP-1 complex behaves like the progelatinase A-TIMP-2 complex and the progelatinase B-TIMP-1 complex in that it is an inhibitor for active metalloproteinases (MMPs) and, after activation, a gelatinase with a pronouncedly reduced activity. When the monomer/lipocalin/TIMP-1 complex inhibits an MMP, a quaternary complex monomer/lipocalin/TIMP-1/MMP is generated which after activation shows a sixfold higher proteolytic activity than the active ternary complex.
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PMID:Progelatinase B forms from human neutrophils. complex formation of monomer/lipocalin with TIMP-1. 892 88

Liver fibrosis and its end stage sequelae cirrhosis represent a major worldwide health problem. By definition progressive fibrosis occurs when the rate of matrix synthesis exceeds matrix degradation. Considerable evidence suggests that the hepatic stellate cell is central to the fibrotic process. During liver injury these cells transform from a quiescent retinoid filled phenotype to a proliferative myofibroblast like cell. In this 'activated' phenotype the HSC is the major source of the interstitial collagens, which characterize fibrosis. Recent work suggests that the HSCs are also a source of matrix degrading metalloproteinase (MMPs), indicating that, together with other cells, hepatic stellate cells (HSC) could participate in matrix remodelling. However, HSC activation in tissue culture models and in vivo is also associated with expression of the powerful MMP inhibitors: tissue inhibitors of metalloproteinases 1 and 2 (TIMP-1 and TIMP-2). TIMP expression has also been demonstrated in fibrotic human liver disease and animal models of liver fibrosis. TIMPs 1 and 2 may therefore promote progression of hepatic fibrosis through inhibition of matrix degradation.
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PMID:Tissue inhibitors of metalloproteinases in liver fibrosis. 907 40


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