Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.17 (MMP-3)
 3,419 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

E1A genes deficient in the carboxy-terminal exon can cooperate with activated ras oncogenes to induce transformation of rat embryo fibroblasts. However, the resulting transformed foci show a distinct appearance characterized by a decreased adhesion of the cells to the substrate. Here, we demonstrate that cell lines derived from foci showing the variant morphology are defective in down-regulation of stromelysin 1 metalloprotease expression and show an increased invasive propensity compared with cells transformed by wild-type E1A. The altered focus morphology, the high invasive propensity and the elevated stromelysin 1 expression were abrogated by glucocorticoid treatment. Our results show that E1A functions necessary for transformation and inhibition of invasive properties may be separated, and indicate that a 23 amino acid serine/threonine-rich region within the E1A carboxy-terminal exon is required for efficient repression of metalloprotease expression in transformed cells.
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PMID:Enhanced invasive properties of rat embryo fibroblasts transformed by adenovirus E1A mutants with deletions in the carboxy-terminal exon. 153 46

Chymase, a potent secretagogue for airway gland serous cells, is stored in secretory granules and released from mast cells together with proteoglycans. To investigate the hypothesis tha tproteoglycans modulate chymase-induced effects, we studied the influence of proteoglycans purified from dog mastocytoma cells on chymase-induced secretion from cultured bovine airway gland serous cells. Heparin proteoglycans reduced the chymase-induced secretory response, whereas glycosaminoglycans and chondroitin sulfate proteoglycans had less of an effect. Chymase released together with proteoglycans from activated mast cells caused secretion comparable to that caused by purified chymase reconstituted with purified proteoglycans. Despite partial inhibition by exocytosed proteoglycans, the secretagogue activity of chymase remains substantial compared to that of histamine. However, proteoglycans virtually abolished chymase-induced degradation of the products of serous cell secretion. Although the secretagogue and proteoglycanase activities of chymase are inhibited by most classes of mast cell granule-associated glycans, the amidolytic activity of chymase toward tripeptide 4-nitroanilide substrates is augmented. These findings suggest that mast cell proteoglycans modulate the secretagogue, proteoglycanase, and peptidase activity of chymase, and the results predict that the extent of this modulation in vivo depends on the nature of the proteoglycans with which chymase is released from mast cells.
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PMID:Mast cell proteoglycans modulate the secretagogue, proteoglycanase, and amidolytic activities of dog mast cell chymase. 157 74

Degradation of proteoglycans is an initial change in osteoarthritic cartilage. Matrix metalloproteinase-3 (MMP-3; stromelysin) capable of degrading cartilage proteoglycans and type IX collagen was immunolocalized in osteoarthritic and normal cartilage. Immunohistochemical studies showed MMP-3 in chondrocytes of the superficial and transition zones in approximately 90% of osteoarthritic cartilage (60 of 67 samples) and in 31% of those of the superficial zone in some normal cartilage (4 of 13 samples). MMP-3 staining correlated directly with the histological histochemical scores of Mankin and with proteoglycan depletion, up to a certain grade of severity. Chondrocytes in the deep radial zone, clusters, and osteophytes were immunostained only when proteoglycan depletion and fissures affected them. Culture media from osteoarthritic cartilage contained significantly higher levels of metalloproteinase activity that was identified as MMP-3 by immunoblotting and lower amounts of tissue inhibitor of metalloproteinases compared with those in the control samples. MMP-3 was also immunolocalized in the lining cells of most osteoarthritic synovium (20 of 23 specimens, 87%) with a direct correlation with scores of inflammatory cell infiltration in the synovium, but it was not detected in the normal synovium. Light and electron microscopic studies demonstrated that MMP-3 digests proteoglycan aggregates in human articular cartilage. Treatment of normal and osteoarthritic cartilage slices with tumor necrosis factor-alpha and/or interleukin-1 alpha increased the number of MMP-3-immunoreactive chondrocytes and the intensity of the staining. These data suggest that MMP-3 produced by the chondrocytes and synovial lining cells under stimulation with these cytokines may be important in proteoglycan degradation in human ostoearthritic cartilage.
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PMID:Localization of matrix metalloproteinase 3 (stromelysin) in osteoarthritic cartilage and synovium. 160 38

Rabbit uterine cervical fibroblasts produced a large amount of matrix metalloproteinases (MMPs) such as collagenase (MMP-1) and stromelysin (MMP-3) and a small relatively amount of tissue inhibitor of metalloproteinases (TIMP). When cells were treated with progesterone or oestradiol-17 beta, both steroids concurrently decreased the level of procollagenase and prostromelysin in the culture media and the steady-state levels of the respective mRNAs. On the other hand, the level of TIMP in the culture media and the steady-state level of its mRNA were simultaneously increased by these steroids. Similarly, the suppression of production of MMPs and the augmentation of TIMP production by both steroids were observed with interleukin 1 (IL-1)-treated cells, but the action of progesterone was more effective than that of oestradiol-17 beta in the IL-1-untreated and -treated cells. These results suggest that collagenolysis in uterine cervical fibroblasts is negatively regulated by steroid hormones via the acceleration of TIMP production and the suppression of synthesis of MMPs at the pretranslational level.
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PMID:Hormonal regulation of collagenolysis in uterine cervical fibroblasts. Modulation of synthesis of procollagenase, prostromelysin and tissue inhibitor of metalloproteinases (TIMP) by progesterone and oestradiol-17 beta. 164 18

Serpins encompass a superfamily of proteinase inhibitors that regulate many of the serine proteinases involved in inflammation and hemostasis. In vitro, many serpins are catalytically inactivated by proteinases that they do not inhibit, leading to the concept of proteolytic down-regulation of serpin inhibitory capacity. The extent to which down-regulation of serpin activity occurs in vivo is debated, since little is known of the rates at which the process occurs. To address this debate, we have measured the rates of inactivation of three serpins, alpha 1-proteinase inhibitor (alpha 1PI), alpha 1-antichymotrypsin (alpha 1ACT), and antithrombin III (ATIII), by three human matrix metalloproteinases (MMPs-1, -2, and -3) thought to be involved in tissue destruction and repair. Our object was to establish a working kinetic model which can be used to predict whether serpin inactivation by these proteinases is likely to occur in vivo. We determined the rates of inactivation of these three serpins by each of the MMPs and compared these to rates of inhibition of the MMPs by an endogenous inhibitor, alpha 2-macroglobulin. An equation designed to predict the extent of substrate hydrolyzed by an enzyme in the presence of an enzyme inhibitor gave the following predictions of the inactivation in vivo: (i) ATIII is unlikely to be inactivated by the MMPs. (ii) MMP-2 (72-kDa gelatinase/type IV collagenase) is unlikely to inactivate any of the three serpins. (iii) MMP-1 (tissue collagenase) will inactivate alpha 1PI and alpha 1ACT only when its concentration saturates that of its controlling inhibitors. (iv) MMP-3 (stromelysin) may inactivate small amounts of alpha 1PI and more significant amounts of alpha 1ACT, even in the presence of its controlling inhibitors. Any physiologic or pathologic inactivation of these serpins by these MMPs that occurs in vivo will probably be due to MMP-3, and will likely only take place in tissues and inflammatory loci where the concentration of MMP inhibitors is depressed.
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PMID:Kinetics and physiologic relevance of the inactivation of alpha 1-proteinase inhibitor, alpha 1-antichymotrypsin, and antithrombin III by matrix metalloproteinases-1 (tissue collagenase), -2 (72-kDa gelatinase/type IV collagenase), and -3 (stromelysin). 165 20

1. Atherosclerosis and aneurysm of the abdominal aorta are associated with thinning of the medial connective tissue. We have investigated the presence of the connective-tissue-degrading metalloproteinases in homogenates prepared from atherosclerotic, aneurysmal and control aortic media. 2. Gelatinase activity was much increased in homogenates from atherosclerotic and aneurysmal aorta [10.9 +/- 1.8 and 13.3 +/- 3.3 micrograms of gelatin hydrolysed h-1 (mg of protein)-1 respectively]. This gelatinase activity was highest at the luminal aspect of the aortic media, where the activity increased three- to five-fold after the destruction of alpha 2-macroglobulin. Zymograms demonstrated the principal gelatinase in atherosclerotic aorta to have a molecular mass of about 92 kDa, whereas in aneurysmal aorta there was a spectrum of gelatinase activity from 92 to 55 kDa. 3. Collagenase and stromelysin (proteoglycanase) could be detected by immunoblotting in homogenates of aneurysmal aorta, but rarely in atherosclerotic aorta and never in control aorta. Collagenase and stromelysin activities were low, but increased two- to three-fold after the destruction of tissue inhibitor of metalloproteinases. Collagenase and stromelysin activities were highest at the adventitial aspect of aneurysmal media. 4. The secretion of gelatinase by inflammatory cells at the intima of diseased aorta could have a pathological role in establishing atherosclerotic plaques and medial thinning. Secretion of collagenase, gelatinase and stromelysin from the adventitia could accelerate connective tissue degradation in the media of aneurysmal aorta.
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PMID:Metalloproteinases in degenerative aortic disease. 165 68

Several N-carboxyalkyl peptides were synthesized and tested as inhibitors of pig synovial collagenase, 72-kDa gelatinase and stromelysin (matrix metalloproteinases MMP-1, MMP-2, and MMP-3). The most potent of the series, CH3CH2CH2(R,S)CH(COOH)-NH-Leu-Phe-Ala-NH2, competitively inhibited cleavage of dinitrophenyl-Pro-Leu-Gly-Leu-Trp-Ala-D-Arg-NH2 at the Gly-Leu bond by MMP-1 and MMP-2 (KI = 30 and 40 microM, respectively). A similar inhibitory potency was found for MMP-1 with soluble Type I collagen and MMP-3 with substance P as substrate. The inhibitor was coupled to EAH-Sepharose 4B through a C-terminal amide. In the presence of 2 M NaCl at pH 7.2, this matrix bound MMP-1, MMP-2, and MMP-3 from concentrated culture medium of pig synovial membranes. The enzymes coeluted at pH 4.1 and subsequently were resolved by chromatography on DEAE-Sephacel and heparin-Sepharose. Purified MMP-1 catalyzed the o-phenanthroline-sensitive cleavage of collagen into TCA and TCB fragments as well as slower hydrolysis of the alpha 2 chain. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis of MMP-1 indicated a predominant polypeptide of approximately 44 kDa and minor species of approximately 24 and 21 kDa. The 44-kDa species and one of the smaller polypeptides reacted with an antiserum to residues 195-207 of human fibroblast MMP-1, indicating that porcine MMP-1 contains a similar sequence and that the smaller components were probably derived from MMP-1. Neither MMP-2 nor MMP-3 reacted with this antiserum. Purified porcine MMP-2 degraded gelatin but not collagen and exhibited an apparent Mr of approximately 71 kDa. Additional smaller polypeptides were present, one of which may correspond to tissue inhibitor of metalloproteinases. MMP-3 showed doublets of approximately 47/46 and 26/25 kDa and cleaved substance P at the Gly6-Phe7 bond. This procedure provides a rapid means of obtaining all three MMPs from one source in approximately 15% yield each.
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PMID:Application of N-carboxyalkyl peptides to the inhibition and affinity purification of the porcine matrix metalloproteinases collagenase, gelatinase, and stromelysin. 165 8

The effects of several nonsteroidal antiinflammatory drugs, used at concentrations achievable in synovial fluid, on human osteoarthritic (OA) cartilage metallo-protease activity in vitro was studied. Acetaminophen and ketoprofen had no effect; sodium salicylate, indomethacin, and diclofenac slightly decreased proteoglycanase activity. Piroxicam and tenoxicam suppressed proteoglycanase activity by 48.2% and 68.3%, respectively, and suppressed collagenase activity by 19.1% and 36.8%, respectively. Use of these NSAIDs may help to decrease cartilage catabolism in patients with OA.
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PMID:In vitro effect of nonsteroidal antiinflammatory drugs on proteoglycanase and collagenase activity in human osteoarthritic cartilage. 165 6

The effects of several antirheumatic drugs on the activity of degradative enzymes in normal and pathologic knee joint cartilage and on the proliferative activity of synovial tissue cells were studied. Inflammatory arthropathy was induced in rabbits by intraarticular papain administration. Elevated contents of proteoglycanase and collagenase, together with an increase in serine and cysteine proteinase inhibitors, were found in animals with papain-induced arthropathy. Inflammation also accelerated the rate of proliferation of cells present in the synovial tissue. In the treated animals, the reduction in enzyme activity, decrease in inhibitor content and decreased DNA proliferation rate were registered to a different degree. The suppression of protein synthesis by nonsteroidal antiinflammatory drugs may explain our findings. The best therapeutic results were achieved with glycosaminoglycan polysulphate (Arteparon).
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PMID:Effect of selected antirheumatic drugs on the metabolism of cartilage and synovial tissue in experimental arthropathy. 165 45

Two zymogens of matrix metalloproteinases (MMPs), proMMP-1 (tissue procollagenase) and proMMP-3 (prostromelysin) were isolated from the culture medium of human rheumatoid synovial fibroplasts and their activation mechanisms by proteinases and 4-aminophenylmercuric acetate (APMA) were studied by kinetic and sequence analyses. Both zymogens were activated by unique stepwise activation mechanisms through which sequential processing events occur in the propeptide regions. The initial cleavage sites attacked by activator proteinases are located in the middle of the propeptides at Glu33-Lys-Arg-Arg-Asn37 in proMMP-1 and Phe34-Val-Arg-Arg-Lys-Asp39 in proMMP-3. The initial products of proMMP-1 generated by proteinases then undergo further autocleavage of the Thr64-Leu65 bond. The treatment of proMMP-1 and proMMP-3 with APMA results in the intramolecular cleavage of the Val67-Met68 and Glu68-Val69 bonds, respectively. The removal of a portion of propeptides results in conformational changes around the Gln80-Phe81 and His82-Phe83 bonds in respective intermediates of MMP-1 and MMP-3 and render them to rapid specific cleavage by MMP-3 to generate stable, fully active enzymes.
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PMID:Stepwise activation mechanisms of the precursors of matrix metalloproteinases 1 (tissue collagenase) and 3 (stromelysin). 166 84


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