Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.35 (matrix metalloproteinase 9)
 2,207 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Primary cultures of adherent rheumatoid synovial cells (ASC) are comprised of variable proportions of fibroblasts, macrophages and stellate cells (activated fibroblasts). These cultures were shown to produce the metalloproteinases stromelysin-1 (MMP-3), gelatinase A (MMP-2) and gelatinase B (MMP-9) by Western blotting and zymography techniques. Immunolocalisation studies showed that MMP-3 was mainly produced by the fibroblastic cells whereas MMP-9 was restricted to macrophages (CD68 positive). Subcultured synovial fibroblasts, devoid of macrophages, did not produce MMP-9 as judged by zymography and immunolocalisation; but when stimulated with phorbol myristate acetate and interleukin-1 alpha both MMP-9 and MMP-3 were co-expressed. These 'activated' fibroblasts assumed a dendritic or stellate morphology, which in localisation studies was usually associated with enhanced enzyme production. Immunolocalisation studies of rheumatoid synovial tissue showed that relatively few cells were positive for MMP-3 and MMP-9. Localisation of MMP-9 corresponded to a proportion of macrophages positive for the CD68 marker throughout the synovial tissue. MMP-3 localisation was not associated with the macrophage marker, but was observed in both the synovial lining layer and deeper stromal locations. Widespread distribution of both enzymes was not observed in fresh tissues, but this increased in tissues subjected to short-term explant cultures. Thus, both in vitro and in vivo studies indicated that synovial fibroblasts or B-cells are effective producers of MMP-3 whereas macrophages elaborate MMP-9, observations that demonstrated different metalloproteinase phenotypes under similar environmental conditions.
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PMID:Differential expression of gelatinase B (MMP-9) and stromelysin-1 (MMP-3) by rheumatoid synovial cells in vitro and in vivo. 835 91

A proform of high molecular weight type IV collagenase was isolated and purified 1230-fold from human metastatic carcinoma tissue. Like matrix metalloproteinases (MMPs), the enzyme was activated by trypsin and degraded type IV collagen and gelatin at a neutral pH, the activity was inhibited by EDTA and o-phenanthroline. However, the molecular weight was much higher than MMPs which degraded type IV collagen, gelatinase A (MMP-2; 72 kDa gelatinase/type IV collagenase) (EC 3.4.24.24), gelatinase B (MMP-9; 92 kDa gelatinase/type IV collagenase) (EC 3.4.24.35), stromelysin-1 (MMP-3; 57 kDa) (EC 3.4.24.17) and stromelysin-2 (MMP-10; 57 kDa) (EC 3.4.24.22). The other significant difference from MMPs was that the enzyme was not activated by 4-aminophenylmercuric acetate nor inhibited by TIMP. Taking together these results, this high molecular weight type IV collagenase might be a newly found enzyme different from MMPs or might have the same configuration as MMPs already reported.
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PMID:Isolation and characterization of a high molecular weight type IV collagenase isolated from human carcinoma tissue. 838 26

We examined the production and tissue localization of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) in gastric carcinoma tissues. MMP-1 (tissue collagenase), MMP-9 (gelatinase B) and TIMP-2 were immunolocalized in carcinoma cells and MMP-2 (gelatinase A) on tumor cell membranes, whereas no or little immunostaining for MMP-3 (stromelysin-1) and TIMP-1 was seen in carcinoma cells. Stromal cells in carcinoma tissue were also positively stained for these MMPs and TIMPs. MMP-2 immunostaining was observed exclusively on advanced gastric carcinoma cells and correlated with vascular invasion by tumor cells. Sandwich enzyme immunoassays revealed enhanced production of MMP-1, MMP-2, MMP-3, MMP-9 and TIMP-1 by carcinoma tissues. Gelatinolytic activities were significantly higher in carcinoma samples than in normal controls. Using gelatin zymography, active forms of MMP-2 and MMP-9 were more frequently detected in carcinoma tissue, and the activation rate of the zymogen of MMP-2 (proMMP-2), but not that of proMMP-9, correlated well with degree of local invasion and lymphatic permeation. Our data indicate an enhanced production of 4 MMPs in gastric carcinoma tissue and suggest that activation of pro-MMP-2 may be a key step for spreading of gastric carcinoma cells.
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PMID:Enhanced production of matrix metalloproteinases and activation of matrix metalloproteinase 2 (gelatinase A) in human gastric carcinomas. 860 68

Gelatinolytic metalloproteinases implicated in connective tissue remodeling and tumor invasion are secreted from several types of cells in the form of inactive zymogens. In this report, characterization of gelatinase activity secreted by the BR line of dog mastocytoma cells reveals a phorbol-inducible, approximately 92-kD, Ca2+ - and Zn2+ -dependent proenzyme cleaved over time to smaller, active forms. Incubation of cells with the general serine protease inhibitor, PMSF, prevented proenzyme cleavage and permitted its purification free of activation products. The NH2-terminal 13 amino acids of the purified mastocytoma progelatinase are 50-67% identical to those of human, mouse, and rabbit 92-kD progelatinase (gelatinase B; matrix metalloproteinase-9). Degranulation of mastocytoma cells using ionophore A23187 greatly accelerated proenzyme cleavage, suggesting that a serine protease present in secretory granules hydrolyzed the progelatinase to active fragments. To identify the activating protease, cells were coincubated with ionophore and a panel of selective serine protease inhibitors. Soybean trypsin inhibitor and succinyl-L-Ala-Ala-Pro-Phe-chloromethylketone, which inhibit mast cell chymase, prevented progelatinase activation. Inhibitors of tryptase and dog mast cell protease (dMCP)-3, i.e., aprotinin or bis(5-amidino-2-benzimidazolyl) methane (BABIM), did not. In further experiments using highly purified enzymes, mastocytoma cell chymase activated 92-kD progelatinase in the absence of other enzymes or cofactors; tryptase and dMCP-3, however, had no effect. These data demonstrate that dog mastocytoma cells secrete a metalloproteinase related to progelatinase B that is directly activated outside of the cell by exocytosed chymase, and provide the first demonstration of a cell that activates a matrix metalloproteinase it secretes by cosecreting an activating enzyme. In mastocytomas, this pathway may facilitate tumor invasion of surrounding tissues, and in normal mast cells, it could play a role in tissue remodeling and repair.
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PMID:Dog mastocytoma cells secrete a 92-kD gelatinase activated extracellularly by mast cell chymase. 860 22

Immunolocalization of matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinases (TIMPs) in periarticular tissues of beta 2-microglobulin amyloidosis patients was investigated. MMP-1 (interstitial collagenase) the most strongly expressed of the MMPs, was localized in the synovial lining cells, mesenchymal cells in granulation tissue and nodular amyloid deposits, and chondrocytes within areas of cartilage erosion. Expression of MMP-1 was correlated with the degree of macrophage infiltration and synovial cell hyperplasia, but it was not correlated with the degree of amyloid deposition or haemodialysis period. Expression of MMP-1 appeared more intense than that of TIMP-1 and TIMP-2 in highly inflammatory cases. MMP-2 was mildly expressed in the interstitial fibroblasts and MMP-3 was faintly stained in the extracellular matrix of the synovial membrane. MMP-9 (gelatinase B) was found to be strongly positive in the osteoclasts which increased in the progressing osteolytic lesion from the destructive arthropathy. These results suggest involvement of MMPs in inflammation with an imbalance between expression of MMPs and TIMPs being closely related to pathogenesis of the destructive arthropathy.
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PMID:Increased matrix metalloproteinases as possible cause of osseoarticular tissue destruction in long-term haemodialysis and beta 2-microglobulin amyloidosis. 864 67

Matrix metalloproteinases (MMPs) and interleukin 1 (IL-1) are implicated in inflammation and tissue destruction, where IL-1 is a potent stimulator of connective tissue cells to produce the extracellular matrix-degrading MMPs. Here, we report that IL-1beta, but not IL-1alpha, is degraded by MMP-1 (interstitial collagenase), MMP-2 (gelatinase A), MMP-3 (stromelysin 1), and MMP-9 (gelatinase B). This degradation was effectively blocked by tissue inhibitor of metalloproteinases (TIMP)-1. When IL-1beta was treated with MMPs it lost the ability to enhance the synthesis of prostaglandin E2 and pro-MMP-3 in human fibroblasts. The primary cleavage site of IL-1beta by MMP-2 was identified at the Glu25-Leu26 bond. These results suggest that IL-1beta stimulates connective tissue cells to produce MMPs, but activated MMPs in turn negatively regulate the activity of IL-1beta.
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PMID:Degradation of interleukin 1beta by matrix metalloproteinases. 866 97

Immunolocalization techniques were used to examine the distribution of the matrix metalloproteinases gelatinase B and stromelysin 1 in human endometrial specimens, taken across the normal menstrual cycle. Gelatinase B was produced by glandular epithelial cells for approximately 7 days during the proliferative phase, with polymorphonuclear leucocytes, macrophages and eosinophils providing most of this enzyme at menstruation. There was no evidence that gelatinase B is produced by stromal cells or mast cells during the cycle. Immunoreactive gelatinase B in glandular epithelial cells was greatest during the late proliferative phase and just after ovulation; its presence in glandular secretion and the uterine fluid was optimal during the peri-implantation phase. Gelatinase B was clearly associated with an influx of polymorphonuclear leucocytes, macrophages and eosinophils just before, and during, menstruation. In contrast, immunostaining for stromelysin 1 was much weaker than that for gelatinase B, and was present only around stromal cells and limited to microfocal locations at times coincident with stromal oedema (days 8-10 and 21-22). Both enzymes were widely distributed in specimens just before and during menstruation, and were particularly prominent in connective tissue stroma and vascular basement membranes. Specimens at the early proliferative stage were devoid of both enzymes. The data provide further evidence supporting a role for metalloproteinases in endometrial biology, not only in matrix remodelling during the cycle, but also in glandular secretions potentially relevant to blastocyst recognition and implantation. Our observations emphasize the functional importance of specific cell types and the temporal regulation of gelatinase B and stromelysin 1 throughout the normal menstrual cycle.
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PMID:Immunolocalization of the matrix metalloproteinases gelatinase B and stromelysin 1 in human endometrium throughout the menstrual cycle. 869 33

We examined production and tissue localization of matrix metalloproteinase (MMP)-1 (tissue collagenase), MMP-2 (gelatinase A), MMP-3 (stromelysin-1), MMP-9 (gelatinase B), tissue inhibitors of metalloproteinase (TIMP)-1 and TIMP-2 in human breast carcinomas. In more than half of the cases, MMP-1, MMP-2, MMP-9, TIMP-1 and TIMP-2 were immunolocalized in carcinoma cells and MMP-2 was on the carcinoma cell membranes as well, whereas MMP-3 was positively stained in less than 15% of the cases. MMP-1 staining in carcinoma cells was significantly higher in scirrhous carcinoma than in other types of carcinoma. MMP-9 expression was remarkably higher in the carcinoma cases with lymphnode metastasis than in the non-metastatic cases. MMP-3 was mainly expressed in T-lymphocytes infiltrated in the tumor stroma. Stromal fibroblasts were positive for all these MMPs except for MMP-3. The TIMP-1 levels released into the culture media by carcinoma tissues were significantly lower than those by fibroadenoma tissues, although there were no significant differences in the levels of MMP-1, MMP-2, MMP-9 and TIMP-2. Gelatin zymographical analyses showed that the activation rate of the zymogen of MMP-2 (proMMP-2) is significantly higher in the more advanced carcinoma group with lymphnode metastasis than in the metastasis-negative and fibroadenoma groups. These data indicate that MMP-1, MMP-2 and MMP-9 are highly expressed in human breast carcinoma tissue and suggest that activation of proMMP-2 may be an indicator of lymphnode metastasis of the breast carcinoma.
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PMID:Production of matrix metalloproteinases and tissue inhibitors of metalloproteinases in human breast carcinomas. 876 24

Thickening of the tubular basement membrane is one of the hallmarks of the polycystic kidney disease (PKD). The present study was conducted to investigate the potential role of the matrix metalloproteinase-2 (MMP-2) and its specific tissue inhibitors (TIMP-1 and TIMP-2) in the accumulation of matrix components in PKD. As a model of PKD, two-month-old heterozygous Han:SPRD rats, which are at an early stage of cystogenesis, were used. MMP-2, but not MMP-9 (gelatinase B) nor MMP-3 (stromelysin) could be detected in proximal tubules of the normal rat kidney. The presence of the inhibitors TIMP-1 and TIMP-2 was confirmed on the mRNA level. In tubules from PKD rats MMP-2 activity was lower (31 +/- 8 vs. 58 +/- 7 U/prep., N = 9, P < 0.05), mRNA of MMP-2 was reduced 4.2 +/- 0.6-fold (N = 4, P < 0.05) and enzyme protein was depressed 3.8 +/- 0.8-fold (N = 4, P < 0.05). By contrast, TIMP-1 mRNA was 9.0 +/- 1.1-fold and TIMP-2 mRNA 3.8 +/- 0.7-fold (N = 4, P < 0.05) elevated over controls. Cyst fluid from homozygous rats contained MMP-2 protein and activity. These findings indicate that tubular MMP-2 activity is reduced in PKD, due to down-regulation of MMP-2, up-regulation of TIMP-1 and TIMP-2, and luminal secretion of the enzyme. It is conceivable that these alterations relate to the enhanced matrix accumulation observed in the evolution of PKD.
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PMID:Tubular gelatinase A (MMP-2) and its tissue inhibitors in polycystic kidney disease in the Han:SPRD rat. 877 Sep 51

We have examined the regulation of precursor of matrix metalloproteinase 9 (proMMP-9)/progelatinase B production by tumor necrosis factor alpha (TNFalpha) and interleukin 1alpha (IL-1alpha) using human uterine cervical fibroblasts. TNFalpha, but not IL-1alpha, induces the production of proMMP-9 in the cervical cells. IL-alpha, however, suppresses the TNFalpha-induced proMMP-9 production. 12-0-tetradecanoylphorbol 13-acetate (TPA) also stimulates the cervical cells to produce proMMP-9, and IL-1alpha synergistically enhances its production. TNFalpha-induced proMMP-9 production is not mediated by protein kinase C (PKC), whereas the effect of IL-1alpha is through PKC. By contrast, proMMP-3/prostromelysin 1 is up-regulated by TNFalpha or TPA in the presence of IL-1alpha, whose modulation is PKC-dependent. The suppressive effect of IL-1alpha on the TNFalpha-induced proMMP-9 production is a new biological effect of IL-1 on MMP production.
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PMID:Tumor necrosis factor alpha (TNFalpha) induces pro-matrix metalloproteinase 9 production in human uterine cervical fibroblasts but interleukin 1alpha antagonizes the inductive effect of TNFalpha. 877 98


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