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)

Gene expression of matrix degrading enzymes was investigated in surgical specimens of perforated gastric ulcers. In these ulcers, the inflammatory cells infiltrating into the granulation tissue were granulocytes, particularly eosinophils. The extracellular matrix of the stomach wall consists mainly of collagen types I and III, which are selectively degraded by matrix metalloproteinase-1 (MMP-1). MMP-1 mRNA was detected in the cytoplasm of infiltrating cells, suggesting that eosinophils play an important role in ulcer recurrence and in perforation of the stomach wall. The degree of eosinophil infiltration into an ulcer base may be a useful marker for the risk of perforation. Patients showing this marker may benefit from a prophylactic therapy for preventing severe complications. The control of MMP gene expression represents a potential strategy for the treatment of recurrent gastric ulcer.
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PMID:Matrix metalloproteinase gene expression in chronic gastric ulcer: a potential role of eosinophils in perforation. 947 34

To study the extend of ongoing tissue remodelling in end-stage cirrhosis, the expression of different matrix metalloproteinases [interstitial collagenase (MMP-1), Mr 72000 gelatinase (MMP-2), stromelysin-1 (MMP-3) and stromelysin-3 (MMP-11)] and of TIMP-1 was studied in 13 cirrhotic livers explanted at transplantation. The results were compared with those obtained in normal liver. Western blot, northern blot, ELISA, RT-PCR and zymogram analysis were used. Proenzymes of stromelysin-1 and -3, interstitial collagenase and Mr 72000 gelatinase were positive in normal liver, while activated enzymes were not detectable in western blot analysis. In cirrhosis proenzyme levels of the studied MMPs were reduced to a mean of 60-70%, but mRNA expression and gelatin-degrading activity increased. TIMP-1 expression was detectable on mRNA level and by ELISA in normal liver and also increased in cirrhosis. Our results show that mRNA expression of certain matrix metalloproteinases is increased in end-stage liver cirrhosis, while the amount of proenzyme is decreased, indicating enhanced MMP proenzyme turnover. These data suggest that besides increased TIMP-1 activity, altered MMP expression may also play a part in fibroproliferation in liver disease.
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PMID:Comparison of matrix metalloproteinase expression in normal and cirrhotic human liver. 950 60

Programmed expression of matrix metalloproteinases is involved in wound healing in various organs. We have previously demonstrated enhanced expression of collagenase-1, stromelysin-1, matrilysin, and tissue inhibitor of metalloproteinases (TIMP-1) in gastrointestinal ulcerations. To further define the role of matrix-degrading enzymes and their inhibitors in intestinal inflammation and ulcerations, the expression of stromelysin-2 (MMP-10), collagenase-3 (MMP-13), macrophage metalloelastase (HME, MMP-12), and TIMP-3 mRNAs was studied using in situ hybridization and immunohistochemistry in 38 samples representing ulcerative colitis, Crohn's disease, ischemic colitis, and normal intestine. As controls for normally healing intestinal wounds, 12 postoperative samples of rat experimental jejunal anastomoses were also examined. The colitis types studied did not essentially differ in their MMP expression. We found stromelysin-2 mRNA in laminin-5-positive and Ki-67-negative enterocytes bordering the ulcerations. HME was abundantly expressed by macrophages in the vicinity of shedding mucosal epithelium and beneath the necrotic surface of the ulcers. Collagenase-3 and TIMP-3 were expressed by fibroblast-like cells deeper in the remodeling intestinal wall. Expression for stromelysin-2 and collagenase-3 was observed in granulation tissue, but not the epithelium, of the rat anastomoses. Our results suggest a role for stromelysin-2 in epithelial migration and for metalloelastase in macrophage movement and epithelial cell shedding.
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PMID:Distinct expression profiles of stromelysin-2 (MMP-10), collagenase-3 (MMP-13), macrophage metalloelastase (MMP-12), and tissue inhibitor of metalloproteinases-3 (TIMP-3) in intestinal ulcerations. 954 61

The membrane-type 1 matrix metalloproteinase (MT1-MMP) has been reported to mediate the activation of pro-gelatinase A (proMMP-2), which is associated with tumor proliferation and metastasis. MT1-MMP can also digest extracellular matrix (ECM) such as interstitial collagens, gelatin, and proteoglycan and thus may play an important role in pathophysiological digestion of ECM. We studied the inhibitory effect of various hydroxamate MMP inhibitors, including known inhibitors such as BB-94, BB-2516, GM6001, and Ro31-9790, on a deletion mutant of MT1-MMP lacking the transmembrane domain (DeltaMT1) to further characterize the enzyme and develop a selective inhibitor for MT1-MMP. The evaluation of the inhibitory activities of various hydroxamates reveals general structural profiles affecting selectivities toward MMPs. In particular, a longer side chain at the P1' position is preferable for the binding to MMP-2, -3, and -9 and MT1-MMP. For the P2' position, an alpha-branched alkyl group is critical for the binding toward DeltaMT1, while the introduction of a bulky group at the alpha-position of hydroxamic acid seems to diminish the activity against DeltaMT1. Summation of the data on the sensitivity of DeltaMT1 to various hydroxamate inhibitors indicates that (1) the volume of the S1' subsite of DeltaMT1 is similar to that of MMP-2, -3, and -9, which is bigger than that of MMP-1, and (2) the S1 and S2' subsites are narrower than those in other MMPs. On the basis of these results, the hydroxamates with a P1' phenylpropyl and P2' alpha-branched alkyl group were synthesized and evaluated for inhibitory activity. These inhibitors (1h,i) showed strong activity against DeltaMT1 over MMP-1, but no selectivity between DeltaMT1 and MMP-9. These results are explained using molecular modeling studies conducted on MT1-MMP.
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PMID:Inhibition of membrane-type 1 matrix metalloproteinase by hydroxamate inhibitors: an examination of the subsite pocket. 954 12

Renal tubulointerstitial fibrosis may result from a loss of tubulointerstitial volume, which produces a disproportionate increase in the density of matrix. This study examines the relationship between fibrogenesis and collapse in scar formation after experimental renal infection. Escherichia coli were inoculated into the renal cortex of Sprague Dawley rats, with saline substituted in a control group. Glomerular, tubular, and interstitial profile areas were determined. Density of glomerular profiles was used as a measure of tubulointerstitial collapse. Collagen type I, III, and IV expression was examined by in situ hybridization and immunohistochemistry. Myofibroblasts were identified by alpha smooth muscle actin immunohistochemistry, and matrix metalloproteinase-1 (MMP-1) and MMP-2 were localized with appropriate antisera. Acute interstitial edema was followed by increasing density of glomerular profiles, paralleled by loss of interstitial volume and progressive tubular atrophy. Glomerular profile area remained unchanged. Density of glomerular profiles was not temporally related to myofibroblast accumulation. Procollagen alpha 1(I), alpha 1(III), and alpha 1(IV) transcription was focal, spatially related but temporally ordered. Collagen I, III, and IV immunostaining was increased from days 3, 24, and 100, respectively (P < 0.05 versus day 0 and day 100 saline). However, when corrected for glomerular density, collagen I immunostaining decreased between days 24 and 100, whereas collagen III and IV no longer differed from day 0. MMP staining within the lesion was confined to occasional interstitial and epithelial cells throughout. It is concluded that in this model, contraction and collapse of the tubulointerstitial parenchyma has a greater influence than new collagen production on final fibrotic density.
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PMID:Evolution of tubulointerstitial fibrosis in experimental renal infection and scarring. 955 66

Understanding the mechanisms responsible for photodamage to the skin is most important for dermatology. 3-D cultures have been used as tools to mimic the in vivo situation for several years. We irradiated such a system containing human dermal fibroblasts cultured in collagen gels, a well-known model considered to be a dermal equivalent, which reproduces the interaction between cells and the surrounding extracellular matrix. The effects of solar irradiation (315-800 nm) on the steady-state levels of the mRNAs of extracellular matrix components (type I and III collagens) and their degrading enzymes (interstitial collagenase, MMP-1 and stromelysin 1, MMP-3) were measured. Exposure to low levels of solar radiation (0-10 J cm-2 in the UVA, i.e. suberythemal UVA doses) caused a transient decrease in type I procollagen mRNA, an increase in MMP-mRNA, and no change in type III procollagen mRNA steady-state levels. These results describe the early changes in the connective tissue of the skin following exposure to low-level solar stimulation, and may help explain the long-term changes in photodamaged skin.
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PMID:Effects of simulated solar radiation on type I and type III collagens, collagenase (MMP-1) and stromelysin (MMP-3) gene expression in human dermal fibroblasts cultured in collagen gels. 959 12

We show that osteopontin (OPN), bone sialoprotein (BSP) and GRGDSP peptides, in solution, induce activation of metalloproteinase-2 (MMP-2) secreted by human GCT23 giant cell tumour cells. Activation of MMP-2 is RGD sequence dependent, possibly involves anti-alphaVbeta3 integrins, is preceded by a change from spread to rounded cell morphology and is mimicked by the actin depolymerising agent cytochalasin B. Cells that had spread on OPN, BSP and GRGDSP substrata failed to activate MMP-2, but subsequent addition of soluble GRGDSP induced rounding and MMP-2 activation. Activation induced by GRGDSP and cytochalasin B was cell mediated, inhibited by EDTA, tissue inhibitor of metalloproteinase-2 (TIMP-2) and carboxyl terminal MMP-2 consistent with a role for membrane type (MT)-MMP but did not involve urokinase, plasmin or thrombin activity. Activation induced by GRGDSP and cytochalasin B, but not cell rounding, was inhibited by herbimycin A, cycloheximide and actinomycin D, suggesting a role for tyrosine kinases, protein and RNA synthesis, but was not associated with changes in mRNA for MT-MMP-1, MMP-1, MMP-2, TIMP-1 or TIMP-2. GRGDSP and cytochalasin B enhanced levels of membrane-associated pro- and active form MMP-1 and MMP-2 but not MT-MMP-1, stimulated cell surface MMP-1 staining and induced that of MT-MMP-1, MMP-2 and TIMP-2. This was consistent with the possible relocation of constitutive MT-MMP-1 to the cell surface as a prerequisite for subsequent cell surface MMP-2/TIMP-2/MT-MMP-1 complex formation and to the potential induction of conditions favourable for reciprocal cell surface MMP-1/MMP-2 activation. Our data provide a novel insight into interactions between RGD containing bone matrices, GCT cells and MMPs of potential relevance to GCT pathology.
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PMID:Activation of MMP-2 by human GCT23 giant cell tumour cells induced by osteopontin, bone sialoprotein and GRGDSP peptides is RGD and cell shape change dependent. 963 98

Long-term dialysis patients suffer from various complications including atherosclerosis. It has been suggested that metalloproteinases (MMPs) contribute to vascular remodeling during the development and progression of human atherosclerosis. Activated human monocytes have been demonstrated to secrete MMPs. In the present study, we measured levels of MMP mRNA in peripheral blood monocytes obtained from patients on continuous ambulatory peritoneal dialysis (CAPD) or hemodialysis (HD) and chronic-renal-failure patients not undergoing dialysis. Twenty patients with chronic renal failure were not undergoing dialysis, 20 patients were on CAPD, 40 patients were on chronic HD and 20 healthy volunteers served as controls. We used cDNA probes encoding for MMP-1, MMP-2, MMP-3 and MMP-9 and glyceraldehyde phosphate dehydrogenase. Higher levels of MMP-9 mRNA in the peripheral blood monocytes were observed in HD patients than in CAPD patients, undialyzed chronic renal failure patients or healthy controls. MMP-9 mRNA levels at the end of HD were not significantly higher than those at the start of HD. MMP-9 mRNA levels from HD patients did not differ among the types of membranes. We could detect minimal MMP-1, MMP-2 and MMP-3 mRNA expression in monocytes from all groups. Serum gelatinase activity was detectable in all samples; however, no significant differences existed among the groups. In summary, MMP-9 mRNA expression is enhanced in monocytes from HD and CAPD patients, and the enhancement may be, in part, associated with cardiovascular complications, including atherosclerosis, in dialysis patients. This increase in monocyte MMP-9 mRNA levels is lower in CAPD patients that it is in HD patients.
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PMID:Metalloproteinase-9 mRNA expression in monocytes from patients with chronic renal failure. 965 34

In an experimentally-induced DTH model of MS, we examined mRNA and protein expression of a range of MMPs and of TNFalpha to establish the contribution that individual MMPs might make to the pathogenesis. In control rat brain, mRNA for all of the MMPs examined was detectable. However, by immunohistochemistry, only MMP-2 could be detected. In the DTH lesions, significant increases in the level of mRNA expression were observed for MMP-7, MMP-8, MMP-12, and TNFalpha. Where expression of MMP mRNA was increased, there was a corresponding increase in protein expression detected by immunohistochemistry. To determine whether the upregulated MMPs could invoke destructive events in the CNS, highly purified activated MMP-7, MMP-8, and MMP-9 were stereotaxically injected into the brain parenchyma. All provoked recruitment of leukocytes and BBB breakdown. In addition, MMPs 7 and 9 induced loss of myelin staining. In conclusion, specific MMPs are upregulated in DTH lesions; for the most part, measurement of mRNA was a predictor of increased protein expression. From our injections of MMPs, it is clear that the upregulated MMPs in the DTH lesions could participate in the disruption of the BBB, leukocyte recruitment, and tissue damage.
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PMID:Matrix metalloproteinase expression in an experimentally-induced DTH model of multiple sclerosis in the rat CNS. 967 Aug 46

Neutrophil collagenase or collagenase 2 (MMP-8) is unique among the family of matrix metalloproteinases (MMPs) because of its exclusive pattern of expression in inflammatory conditions. At present, no evidence of the occurrence of this enzyme in tissues other than human has been reported. In this work, we have cloned the murine homologue of human collagenase 2. The isolated cDNA contains an open reading frame coding for a polypeptide of 465 amino acids, which is 74% identical to its human counterpart. The mouse collagenase 2 exhibits the domain structure characteristic of several MMPs, including a signal sequence, a prodomain with the cysteine residue essential for enzyme latency, an activation locus with the Zinc-binding site, and a COOH-terminal fragment with sequence similarity to hemopexin. It also contains the three conserved residues (Tyr-209, Asp-230, and Gly-232) located around the Zinc-binding site and are distinctive of the collagenase subfamily. Northern blot analysis of RNAs isolated from a variety of mouse tissues revealed that collagenase 2 is expressed at late stages during mouse embryogenesis, coinciding with the appearance of hematopoietic cells. In addition, collagenase 2 was highly expressed in the postpartum uterus starting at 1 day postpartum and extending up to 5 days. Enzymatic analysis revealed that matrilysin, another MMP overexpressed in uterine tissue, is able to activate murine procollagenase 2. These data suggest that both enzymes could form an activation cascade resulting in the generation of the collagenolytic activity required during the process of massive connective tissue resumption occurring in the involuting uterus.
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PMID:Collagenase 2 (MMP-8) expression in murine tissue-remodeling processes. Analysis of its potential role in postpartum involution of the uterus. 972 11


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