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:3.4.24.35 (matrix metalloproteinase 9)
2,207 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Serine proteases and matrix metalloproteinases have been shown to often cooperate in multiple physiological and pathological processes associated with changes in the extracellular matrix (ECM). We have examined the interaction between the plasminogen activator (PA)-plasmin system and matrix metalloproteinases (MMPs) in HT1080 human fibrosarcoma cells treated with 12-O-tetradecanoyl-phorbol-13-acetate (TPA). While TPA treatment evoked a temporary increased expression of urokinase type PA (uPA), the production of both types of human plasminogen activator inhibitors (PAI) was induced and sustained over 12 h by TPA treatment shifting the protease-protease inhibitors balance in favor of the inhibitors. TPA treatment of HT1080 cells induced the expression of interstitial collagenase (MMP-1) and increased the expression of gelatinase B (MMP-9), tissue inhibitor of metalloproteinases-1 (TIMP-1), and MT-MMP, a membrane-bound activator of progelatinase A (proMMP-2), while MMP-2 and TIMP-2 expression were decreased. Increased MT-MMP expression by TPA treatment was associated with increased activation of proMMP-2. These data show that the regulation of PA-plasmin and metalloproteinase and their specific inhibitors is uncoordinated. In addition, inhibition of the PA-plasmin system by PAI-2 or aprotinin did not prevent the activation of proMMP-2 by TPA, suggesting that plasmin is not involved in MT-MMP-mediated activation of proMMP-2.
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PMID:Independent regulation of matrix metalloproteinases and plasminogen activators in human fibrosarcoma cells. 861 75

The gelatinases (type IV collagenases) are members of the matrix metalloproteinase family that not only have a high degree of structural homology but are known to be nearly identical in their digestion profile against macromolecular substrates. We have shown previously that the preferred cleavage sites in the hydrolysis of type I gelatin, catalyzed by gelatinase A (72 kDa type IV collagenase), are bracketed by hydroxyproline in the P5 and P5' positions. In this report, a kinetic investigation using a series of collagenous dodecylpeptides in which the P5 and P5' hydroxyprolines were systematically varied and used as substrates for recombinant human gelatinase A, we show that replacement with either proline or alanine always resulted in increased Km. In contrast, substitution of the hydroxylated amino acids tyrosine and serine at P5 and P5' reduced the Km significantly, indicating that the hydroxyl moiety of the hydroxyproline is the functional group responsible for favorable enzyme-substrate affinity. This was shown by the kcat/Km ratio, which was doubled by the substitution of serine in that site. Cleavage of the same series of dodecylpeptides by recombinant human gelatinase B (92 kDa type IV collagenase) showed a very different kinetic profile for which no patterns were discernible. In subsequent comparisons of the two enzymes, it was found that gelatinase B cleaved the thiopeptolide substrate AcProLeuGly-S-LeuGly-OC2H5 at double the velocity of gelatinase A. In contrast, gelatinase A digested type I gelatin about 2.5-times faster than gelatinase B. SDS-PAGE analysis of gelatin cleavage products showed different patterns of product peptides for each enzyme. Further comparisons of the proteinases using synthetic peptide substrates with variations in size and in substituents at the P2' site again showed marked kinetic differences. Although these two matrix metalloproteinases seem similar in that they are both gelatinolytic and can degrade a nearly identical battery of macromolecular matrix components including type IV collagen, it is clear from these results that they are very different enzymatically. Since the regulatory portions of gelatinases A and B differ markedly, it has been assumed that the enzymes serve the same function, but respond to different stimuli. The differences in substrate specificity described herein suggest that their proposed physiological roles may require reevaluation.
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PMID:Comparison of cleavage site specificity of gelatinases A and B using collagenous peptides. 862 38

The invasive property of trophoblast cells is dependent on the activity of proteolytic enzymes of the metallo- and serine proteases family. Interleukin-1 (IL-1) was found to be involved in the regulation of these proteases in various systems, serving as an important modulator in trophoblast physiology (e.g. induction of hCG beta, cytokines, and others). Therefore, consideration is given in this report to the role of IL-1 in the regulation of metalloprotease activity in human trophoblasts. Human trophoblast cells were isolated from first trimester placentas by trypsin degradation and Percoll fractionation. Primary cell cultures of first trimester trophoblasts constitutively elaborated two species of collagenase type IV (92 and 72 kDa), as assessed in gelatin matrix. Treatment with IL-1 further augmented the 92-kDa type IV collagenase secretion in a dose-dependent manner. Furthermore, IL-1 significantly (P < 0.01) increased 92-kDa collagenase gene expression by trophoblast cells, as determined by solution hybridization/ribonuclease protection assay. Both the increase in gene expression and protein biosynthesis of the 92-kDa collagenase type IV were neutralized by the soluble IL-1 receptor, indirectly suggesting a receptor-mediated response. Interestingly, transforming growth factor-beta a putative modulator of IL-1 induced effects, was shown to induce the 92-kDa collagenase type IV secretion as well. These results provide indirect evidence supporting the idea that IL-1 and transforming growth factor-beta may play an intermediary role in trophoblast invasion at the feto-maternal interface by regulating trophoblast expression of 92-kDa type IV collagenase, a protease of prime importance in trophoblast invasion.
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PMID:Cytokine-mediated regulation of type IV collagenase expression and production in human trophoblast cells. 876 80

Activation of matrix metalloproteinase (MMP)-2, the 72-kd collagenase IV/gelatinase A, is involved in extracellular matrix remodeling. It has been suggested that a membrane-type MMP (MT-MMP-1) and the tissue inhibitor of metalloproteinase (TIMP)-2 are involved in MMP-2 processing, but the exact mechanism(s) of its activation remains unclear. We have investigated the role of cell-cell cooperation in the activation of pro-MMP-2 in the liver, using pure cultures and co-cultures of hepatocytes and hepatic stellate cells (HSCs). Northern blot analysis and in situ hybridization showed that, in both pure and co-cultures, HSCs, but not hepatocytes, expressed MMP-2, TIMP-2, and MT-MMP-1 mRNA. Zymography analyses revealed the latent form of MMP-2 in medium from 2-day-old pure HSC cultures with higher amounts in medium from hepatocyte/HSC co-cultures. When hepatocytes were added to 10-day-old HSC cultures, the activated form of MMP-2 was detected, concomitantly with the deposition of an abundant extracellular matrix. Incubation of plasma membrane-enriched fractions from hepatocytes with conditioned medium from pure HSC cultures generated the activated species of MMP-2 (62 and 59 kd). Activation of pro-MMP-2 by hepatocyte membranes was inhibited by EDTA, heat, and trypsin but not by serine proteinase inhibitors. These data show that the co-expression of TIMP-2, MMP-2, and MT-MMP-1 by HSCs does not lead to secretion of the activated form of MMP-2. Hepatocytes, which do not express MMP-2, TIMP-2, or MT-MMP-1, induce MMP-2 activation through a plasma membrane-dependent mechanism(s), thus suggesting that cell-cell interactions are involved in this process in vivo.
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PMID:Activation of matrix metalloproteinase-2 from hepatic stellate cells requires interactions with hepatocytes. 900 21

We have investigated the role of proteinases in the developmental program of bone, cartilage, tongue muscle and epithelial differentiation and remodeling in the mandibular arch during murine embryogenesis. Expression of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) was tissue-specific with little or no expression in the epithelium of tooth buds, tongue or oral cavity. Gelatinase A mRNA transcripts were strongly expressed in the perichondrium of Meckel's cartilage and mesenchymal areas of embryonic day 13-15 mandibles, whereas gelatinase B, collagenase-3, TIMP-1 and TIMP-2 mRNA were found primarily in the ossifying areas of the mandibles. The skeletal muscle of the tongue expressed stromelysin-3, TIMP-2 and TIMP-3 mRNA while stromelysin-3, TIMP-2 and gelatinase A were seen in the overlying connective tissue layer. Gelatinase A, gelatinase B, stromelysin-1, urokinase, TIMP-1 and TIMP-2 mRNA and protein activities were also detected in cultured mandibular explants. Culture of day 10 mandibular explants with a hydroxamic acid metalloproteinase inhibitor, but not with inhibitors of metalloendopeptidases (thiorphan and phosphoramidon), serine proteinases (aprotinin), cysteine proteinases (leupeptin) and urokinase (amiloride), altered mandibular morphogenesis dramatically. Development of the tongue (glossogenesis) and cartilage, but not bone or teeth was affected. Formation of the oral sulcus and fusion of the two epithelia of the medial sulcus were inhibited, and number and migration of myoblasts decreased. The resulting 'tongue-tied phenotype' indicates that MMPs are involved in epithelial morphogenesis and the migration of myoblasts to the region of the tongue. Development of the anterior segment of Meckel's cartilage was also inhibited and proteoglycan content of the cartilage was reduced by inhibiting MMPs. Our data suggest that matrix metalloproteinases play a pivotal role in the morphogenesis of structures derived from epithelium (oral sulcus), cranial paraxial mesoderm (tongue) and cranial neural crest (Meckel's cartilage).
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PMID:Matrix metalloproteinases regulate morphogenesis, migration and remodeling of epithelium, tongue skeletal muscle and cartilage in the mandibular arch. 910 68

Insoluble elastin was used as a substrate to characterize the peptide bond specificities of human (HME) and mouse macrophage elastase (MME) and to compare these enzymes with other mammalian metalloproteinases and serine elastases. New amino termini detected by protein sequence analysis in insoluble elastin following proteolytic digestion reveal the P'1 residues in the carboxyl-terminal direction from the scissile bond. The relative proportion of each amino acid in this position reflects the proteolytic preference of the elastolytic enzyme. The predominant amino acids detected by protein sequence analysis following cleavage of insoluble elastin with HME, MME, and 92-kDa gelatinase were Leu, Ile, Ala, Gly, and Val. HME and MME were similar in their substrate specificity and showed a stronger preference for Leu/Ile than did the 92-kDa enzyme. Fibroblast collagenase showed no activity toward elastin. The amino acid residues detected in insoluble elastin following hydrolysis with porcine pancreatic elastase and human neutrophil elastase were predominantly Gly and Ala, with lesser amounts of Val, Phe, Ile, and Leu. There were interesting specificity differences between the two enzymes, however. For both the serine and matrix metalloproteinases, catalysis of peptide bond cleavage in insoluble elastin was characterized by temperature effects and water requirements typical of common enzyme-catalyzed reactions, even those involving soluble substrates. In contrast to what has been observed for collagen, the energy requirements for elastolysis were not extraordinary, consistent with cleavage sites in elastin being readily accessible to enzymatic attack.
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PMID:Elastin degradation by matrix metalloproteinases. Cleavage site specificity and mechanisms of elastolysis. 921 37

The serine proteinase tissue-type plasminogen activator (t-PA) and the metalloproteinase gelatinase B (MMP-9) have recently been demonstrated in MS lesions. Both enzymes are interconnected in an enzyme cascade which contributes to destruction of the blood brain barrier and demyelination and both enzymes are inhibited by D-penicillamine. Metacycline was shown in in vitro experiments to inhibit gelatinase B. The combination of peroral D-penicillamine plus metacycline was evaluated in a double-blind placebo-controlled way in two groups of 10 patients suffering from secondary progressive multiple sclerosis. The major objectives of this pilot trial were to examine the safety of this combination and the possibility of blinding, while the effect on disease progression was considered as a secondary endpoint. Over a follow-up period of 1 year and in this selected patient group, there was no significant improvement in the Expanded Disability Status Scale score (EDSS) as compared with that of the placebo-control group. Toxicity was too high to consider additional trials with this combination of metalloproteinase inhibitors. Although peroral treatment is by most MS patients acknowledged as a major improvement in treatment compliance, one has to await the development of more selective and efficacious protease inhibitors than those used in the combination therapy described here.
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PMID:Toxicity in a double-blind, placebo-controlled pilot trial with D-penicillamine and metacycline in secondary progressive multiple sclerosis. 959 37

Treatment of primary cultured chondrocytes from rabbit articular cartilage with interleukin-1 (IL-1)alpha and plasminogen induced the production of pro-matrix metalloproteinase 1 (proMMP-1/interstitial collagenase), proMMP-3 (stromelysin 1) and proMMP-9 (gelatinase B), as well as their active forms. Human urinary trypsin inhibitor (UTI), a multipotent inhibitor of serine proteases, including plasmin inhibited the activation of proMMP-1, proMMP-3 and proMMP-9 when added to the culture medium together with IL-1alpha and plasminogen, in a dose-dependent manner. Moreover, UTI inhibited the release of proteoglycans induced by IL-1alpha and plasminogen from rabbit articular cartilage explants. These findings strongly suggest that UTI inhibits the destruction of articular cartilage induced by plasmin and/or MMPs. Thus, UTI probably exert an anti-osteoarthritic action via inactivation of proMMPs.
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PMID:Human urinary trypsin inhibitor inhibits the activation of pro-matrix metalloproteinases and proteoglycans release in rabbit articular cartilage. 969 50

Evidence presented in the accompanying article (Gibbs, D. F., T. P. Shanley, R. L. Warner, H. S. Murphy, J. Varani, and K. J. Johnson. 1999. Role of matrix metalloproteinases in models of macrophage-dependent acute lung injury: evidence for alveolar macrophage as source of proteinases. Am. J. Respir. Cell Mol. Biol. 20:1145-1154) implicates alveolar macrophage matrix metalloproteinases (MMPs) in two models of acute lung inflammation in the rat. As a prerequisite to understanding which specific MMPs might be involved in the injury and how they might function, it was necessary to know the spectrum of enzymes present. To this end, alveolar macrophages were obtained from normal rat lungs by bronchoalveolar lavage, placed in culture with and without various agonists, and assessed by a variety of techniques for MMPs. The identification process involved characterization by gelatin, beta-casein, and kappa-elastin zymography, with confirmation of identity by Western blot/immunoprecipitation. Message levels of detected MMPs were assessed by Northern blot. Rat alveolar macrophages were found to produce a low constitutive level of MMP-2 (72-kD gelatinase A) that was only modestly upregulated following stimulation with phorbol myristate acetate, bacterial lipopolysaccharide, or immunoglobulin A-containing immune complexes. Although control cells were found to produce little or no MMP-9 (92-kD gelatinase B) or MMP-12 (metalloelastase), both enzymes were markedly upregulated upon stimulation. In the same stimulated macrophages there was little activity against type I collagen (associated with MMP-13 [collagenase-3] on the basis of Western blotting), no activity suggestive of stromelysin or matrilysin, and no measurable secretion of the serine proteinases, elastase and cathepsin G. These data demonstrate the ability of rat alveolar macrophages to elaborate certain MMPs under proinflammatory conditions, consistent with their possible involvement in the progression of acute inflammation.
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PMID:Characterization of matrix metalloproteinases produced by rat alveolar macrophages. 1034 Sep 32

It has long been speculated that neutrophils deploy proteases to digest subendothelial matrix as they migrate from the bloodstream. Direct evidence for the involvement of proteases in neutrophil transendothelial migration is, however, lacking. To address this issue we used transmission electron microscopy to verify the presence of continuous basal lamina beneath pulmonary endothelial cells grown on microporous filters, and then examined the effects of protease inhibitors on neutrophil migration through the endothelial cells and their associated subcellular matrix. Inhibitors of the two major matrix-degrading protease groups present in neutrophils, the matrix metalloproteinases (MMPs) and serine proteases, were assessed for their ability to modulate neutrophil transendothelial migration in response to the chemoattractant n-formylmethionyl leucylphenylalanine (FMLP). Neither the naturally occurring MMP inhibitor, tissue inhibitor of metalloproteinase-1, nor the hydroxamic acid-based inhibitors GM-6001, BB-3103, or Ro 31-9790 had any significant effect on FMLP-stimulated neutrophil migration across endothelial cells and associated basal lamina, with >/= 80% of neutrophils migrating through the system, even in the presence of inhibitors, at concentrations that totally inhibited all the gelatinase B (MMP-9) released upon stimulation with FMLP. Similarly, with serine protease inhibitors no significant inhibition of neutrophil migration was observed with a naturally occurring inhibitor, secretory leukocyte protease inhibitor, or a low molecular-weight synthetic inhibitor, Pefabloc SC. These results indicate that neither MMP nor serine protease digestion of sub-endothelial matrix is required for successful neutrophil transendothelial migration.
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PMID:Migration of neutrophils across human pulmonary endothelial cells is not blocked by matrix metalloproteinase or serine protease inhibitors. 1034 Sep 40


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