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:3.4.24.23 (MMP)
4,246 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

Entactin is the basement membrane protein which bridges laminin and type IV collagen. Entactin is known to be degraded by serine proteinases, but its susceptibility to matrix metalloproteinases has not been determined. We have studied the capacity of three matrix metalloproteinases (interstitial collagenase, 92-kDa gelatinase, and matrilysin) to degrade entactin. While all three metalloenzymes cleaved entactin, matrilysin was approximately 100-fold as effective as collagenase and 600-fold as effective as 92-kDa gelatinase. The Km of matrilysin for entactin was 8.9 x 10(-7) M. A Vmax of 21 molecules of entactin degraded/molecule of matrilysin/min at 37 degrees C was observed. An Arrhenius plot relating matrilysin's catalytic activity to temperature was linear from 15 to 37 degrees C and indicated an activation energy of 10,060 calories/mol. Matrilysin produced multiple, but distinct, cleavages in entactin resulting in peptide fragments ranging from 115 to 29 kDa. The precise sites of cleavage of six fragments were determined by Edman degradation. Cleavage sites consistently occurred amino-terminal to leucine or isoleucine. These data indicate that entactin is a substrate for matrix metalloproteinases. The effectiveness of matrilysin is noteworthy, however, particularly in relation to the minimal ability of other much more well described matrix metalloproteinases to attack this substrate. Our results suggest a potentially important role for matrilysin in disruption of basement membranes by tumor or inflammatory cells.
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PMID:Degradation of entactin by matrix metalloproteinases. Susceptibility to matrilysin and identification of cleavage sites. 838 May 88

Programmed expression of several matrix metalloproteinases is an important feature of cutaneous wound healing. To study whether this also applies to gastrointestinal ulcer healing, we used in situ hybridization with 35S-labeled probes to localize sites of collagenase, stromelysin-1, and matrilysin expression in 26 samples representing peptic ulcers, Crohn's disease, and ulcerative colitis. In contrast to skin wounds, collagenase mRNA was not detected in the surface epithelium bordering gastrointestinal ulcer areas. However, together with stromelysin-1 mRNA, it was abundantly expressed by the granulation tissue in all types of ulcers. Signal for matrilysin mRNA and protein was detected in the mucosal epithelium bordering the ulcerations but never in the ulcer stroma. The gut basement membrane was disrupted under the matrilysin-producing epithelial cells as assessed by immunostaining for laminin. Tissue inhibitor of metalloproteinases (TIMP-1) mRNA never co-localized with matrilysin-positive mucosal epithelial cells. These data indicate that matrilysin plays a significant role in epithelial remodelling occurring in gastrointestinal ulcerations whereas collagenase and stromelysin-1 are involved in the reparative processes in the ulcer bed.
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PMID:Enhanced expression of matrilysin, collagenase, and stromelysin-1 in gastrointestinal ulcers. 857 14

Interstitial collagenase (matrix metalloproteinase-1 [MMP-1]) plays an important role in extracellular matrix turnover. Myocardial MMP-1 may contribute to tissue remodelling in the heart. Little is known about collagenase and its regulation in the myocardium. To understand better the nature of this neutral proteinase in the rat myocardium, myocardial collagenase was purified to homogeneity. The purification procedure included a gel-filtration step on Sephacryl S-200 columns and substrate affinity chromatography on type I collagen-Sepharose. Under reducing conditions, collagenase was shown by SDS-PAGE to consist of a single polypeptide chain with a molecular mass of 54 kDa. Purified interstitial collagenase demonstrated a single lytic band on zymography. This band was inhibited by 1,10-phenanthroline (a metal chelator), which indicates that the 54 kDa protein is an MMP. Using a polyclonal antibody to proMMP-1, purified collagenase was characterized by immunoblot analysis. A single band of purified interstitial collagenase was observed on Western blot analysis. This indicated that the purified proenzyme was collagenase. Sequence analysis on cyanogen bromide-digested fragments of latent MMP-1 suggested that the active site sequence of rat myocardial MMP-1 is similar to that of the rat osteoblast collagenase, human skin fibroblast collagenase and Serratia proteinase. The substrate specificity of the purified collagenase was measured against fluorescent-labelled type I collagen. It was observed that after activation, purified collagenase was capable of degrading type I collagen in a time-dependent manner. The half-time for collagen degradation was estimated to be less than 30 s. These results suggest that collagenase is present in the normal adult rat myocardium and that collagen turnover may be regulated by this neutral metalloproteinase. A simple two-step purification protocol is demonstrated for interstitial collagenase. This procedure can be used for routine MMP-1 preparation from tissue sources.
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PMID:Myocardial collagenase: purification and structural characterization. 860 38

Induction of stromelysin and collagenase mRNAs in response to phorbol myristate acetate (PMA) and autocrine factors (CAF) was compared in primary cultures of lapine synovial fibroblasts and an immortalized line of these cells known as HIG-82. In both cell types, message induction was quicker for CAF than for PMA. Appearance of both stromelysin and collagenase mRNAs occurred earlier in HIG-82 cells and, unlike primary cells, HIG-82 cells partially resisted inhibition by cycloheximide. To determine whether differences in AP-1 activity could account for these observations, the induction of c-fos and c-jun mRNAs was studied in conjunction with gel shift assays for AP-1 binding. Both inducers increased the abundance of c-fos mRNA, although the response was weaker in HIG-82 cells. However, the increase in c-jun mRNA was more marked in HIG-82 cells; furthermore, this increase was sustained for over 6 h. Gel shift assays confirmed that in both types of cells PMA and CAF increased AP-1 binding activity. In primary cells, this activity was sensitive to cycloheximide, but in HIG-82 cells, there was only partial sensitivity to cycloheximide. The gel shift analyses and data from experiments using an AP-1-CAT reporter construct revealed, in many cultures, constitutive AP-1 activity in the absence of stromelysin and collagenase expression, suggesting that AP-1 alone is insufficient for matrix metalloproteinase induction. Antisense oligonucleotides to c-fos and c-jun strongly inhibited the induction of stromelysin mRNA in primary cells treated with PMA, but was only weakly active against message induction in HIG-82 cells. In neither primary cells nor HIG-82 cells did antisense oligonucleotides strongly inhibit stromelysin induction in response to CAF. These data suggest there may exist an AP-1-independent route to message induction or that factors other than c-FOS and c-JUN may be used in certain circumstances. Western blot analyses detected no marked difference between HIG-82 cells and primary cells in their resting levels of c-FOS and c-JUN. Thus the differences reported here between HIG-82 cells and primary cells in their resting levels of c-FOS and c-JUN. Thus the differences reported here between HIG-82 cells and primary cells in the kinetics and cycloheximide sensitivity of MMP induction may reside in their abilities to modify posttranslationally the relevant transcription factors.
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PMID:Effects of immortalization upon the induction of matrix metalloproteinases in rabbit synovial fibroblasts. 863 83

Matrix proteases and the transcription factor c-Ets-1, which regulates in vitro stromelysin 1, collagenase 1, and urokinase type plasminogen activator gene promoters, are frequently expressed in invasive carcinomas. Using in situ hybridization and immunohistochemistry, we analyzed collagenase 1, stromelysins 1 and 3, matrilysin, urokinase type plasminogen activator, and c-Ets-1 gene expression on serial frozen sections of 39 intraepithelial bronchial lesions, including areas of hyperplasia, metaplasia, dysplasia, carcinoma in situ, and corresponding lung carcinomas in 13 patients. In intraepithelial lesions, expression of all matrix proteases was detected in epithelial cells. Conversely, in microinvasive or invasive lesions, a fibroblastic expression was observed. Collagenase 1 and matrilysin were expressed seldomly in intraepithelial lesions and frequently in carcinomas (p = 0.0016 and p < 0.0001, respectively). Stromelysin 1 was expressed inconsistently in 31% of intraepithelial lesions of all grades and in 50% of carcinomas. Stromelysin 3 and urokinase type plasminogen activator were expressed only, but frequently, in preinvasive lesions (dysplasia, carcinoma in situ) and in carcinomas. The expression of stromelysin 3 in fibroblasts started with dysplasia and carcinoma in situ, but was more frequent in invasive than preinvasive lesions (p = 0.0012). c-Ets-1 was more often expressed in carcinomas than in intraepithelial lesions (p < 0.0001) and was always expressed in fibroblasts. Comparing preinvasive lesions adjacent to or at a distance from squamous lung carcinoma, stromelysin 3 epithelial expression was more frequent in preinvasive lesions adjacent to invasive foci than in others (p = 0.036). We conclude that (a) both epithelial expression of matrix proteases in intraepithelial bronchial lesions and their stromal expression in microinvasive and invasive lesions suggest their role in lung tumor development; (b) c-Ets-1 does not act as a transcriptional activator for matrix proteases genes in preinvasion, although it might regulate collagenase 1 gene during lung tumor progression; and (c) matrix proteases might offer new therapeutic targets for chemoprevention of lung cancer.
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PMID:Changes in the expression of matrix proteases and of the transcription factor c-Ets-1 during progression of precancerous bronchial lesions. 868 34

The proteolytic potential of cellular fibronectin fragments issued from a basement membrane hydrolysate was investigated. Three different gelatinase activities (47, 43 and 37 kDa), located by gelatin zymography, were isolated using successively heparin-agarose, gelatin-agarose and immunopurification with polyclonal antibodies directed against bovine plasma fibronectin. These fragments were also characterized using a monoclonal antibody directed against the extra-domain EDA of cellular fibronectin as a probe. A collagenase activity, reliably indicated by the gelatin zymography pattern, was also found using MCA-Pro-Leu-Gly-Leu-DPA-Ala-Arg-NH2, the intramolecularly quenched fluorogenic substrate of collagenases. From these results, cellular fibronectin was found to be able to exhibit a proteolytic function after limited proteolysis. This MMP-like function could be associated with tissue remodeling in both normal and pathological states, such as metastasis, angiogenesis and tissue repair.
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PMID:Immunopurification and characterization of a collagenase/gelatinase domain issued from basement membrane fibronectin. 870 29

We examined metalloproteinase (MMP)-1, -2, -3, and -9 mRNA expression by peripheral blood monocytes from 50 patients with immunoglobulin A (IgA) nephropathy, 20 with membranous nephropathy, 10 with minimal-change nephrotic syndrome, five with focal glomerulosclerosis, 30 with non-IgA proliferative glomerulonephritis, and 40 healthy normal controls who were comparable with regard to age and sex. Monocytes from patients with IgA nephropathy expressed a higher level of MMP-9 mRNA than those from patients with other forms of glomerulonephritis or from healthy controls (MMP-9 to glyceraldehyde-3-phosphate dehydrogenase ratio: IgA nephropathy, 1.68 +/- 0.24; membranous nephropathy, 0.22 +/- 0.08; minimal-change nephrotic syndrome, 0.24 +/- 0.06; focal glomerulosclerosis, 0.32 +/- 0.08; non-IgA proliferative glomerulonephritis, 0.30 +/- 0.12; and healthy controls, 0.16 +/- 0.04). When the biopsy specimens were classified into four grades according to the severity of glomerular and interstitial pathology, highly significant differences were observed among MMP-9 mRNA levels in monocytes from all four groups of patients with IgA nephropathy (grade I, 0.44 +/- 0.09; grade II, 1.06 +/- 0.26; grade III, 2.22 +/- 0.68; grade IV, 2.86 +/- 0.88). In addition, MMP-9 mRNA levels from patients with IgA nephropathy correlated with urinary protein excretion (P < 0.001). However, we detected minimal mRNA expression of MMP-1, -2, and -3 by peripheral blood monocytes from patients with IgA nephropathy or other forms of glomerulonephritis and from normal healthy controls. Our results suggest that increased MMP-9 mRNA expression in circulating monocytes may contribute to the progression of IgA nephropathy.
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PMID:Increased mRNA expression of metalloproteinase-9 in peripheral blood monocytes from patients with immunoglobulin A nephropathy. 871 19

The role of matrix metalloproteinases in parathyroid hormone (PTH)-induced bone resorption was assayed using a fetal rat limb bone culture system. Cotreatment of bones with PTH and recombinant inhibitor of metalloproteinases, TIMP-1, in vitro, inhibited the PTH-stimulated 45Ca release from the limb bones without affecting beta-glucuronidase release. TIMP-1 was fully effective when added during only the final 24 h of a 72 h culture with PTH but was ineffective when added for only the first 24 h of the 72 h culture. In contrast, calcitonin (CT) was effective when added for either the first 24 or the final 24 h of the culture. Using in situ hybridization, the mRNA for collagenase was detected in mononuclear cells of cultured bone. Treatment of the bones with PTH resulted in an increase in the number of cells producing collagenase mRNA, some of which had osteoclastic morphology, PTH also caused a dramatic induction of the mRNA for the 92-kD gelatinase B metalloproteinase in both mononuclear and osteoclastic cells. There was no detectable mRNA for the metalloproteinases stromelysin-1, stromelysin-2, or matrilysin in PTH-treated or control cultures. These results suggest that PTH-induced bone resorption is mediated, at least in part, by the induction of collagenase and gelatinase B mRNA in bone cells.
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PMID:Parathyroid hormone-induced resorption in fetal rat limb bones is associated with production of the metalloproteinases collagenase and gelatinase B. 877 Jun 99


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