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)

Borrelia burgdorferi, the spirochetal agent of Lyme disease, stimulated human peripheral blood monocytes to release pro-matrix metalloproteinase-9 (gelatinase B; pro-MMP-9) and active matrix metalloproteinase-1 (collagenase-1; MMP-1). Human neutrophils also released pro-MMP-9 and a 130-kDa protein with gelatinolytic activity in response to live B. burgdorferi. In addition, U937 cells and human keratinocyte cells were also stimulated to release pro-MMP-9 under the same conditions. However, human umbilical vein endothelial cells (HUVECs) released pro-MMP-9 and pro-MMP-2 in a constitutive manner and were not influenced by live spirochetes. MMPs produced by human monocytes also enhanced the penetration of B. burgdorferi through extracellular matrix component barriers in vitro. Plasmin stabilized on the surface of the Lyme disease spirochete was shown to activate pro-MMP-9 to its active form. This active form was also observed in the plasma of mice infected with a relapsing fever borrelia. These results suggest that borreliae can upregulate MMPs and possibly mediate an activation cascade initiated by plasmin bound to the microbial surface. MMPs may play a role in dissemination of the Lyme disease spirochete and in the pathogenesis of Borrelia infection.
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PMID:Borrelia spirochetes upregulate release and activation of matrix metalloproteinase gelatinase B (MMP-9) and collagenase 1 (MMP-1) in human cells. 1111 37

The matrix metalloproteinase (MMP) and fibrinolytic (plasminogen/plasmin) systems cooperate in many (patho)physiological processes requiring extracellular proteolysis. The effect of MMP-3 (stromelysin-1), MMP-7 (matrilysin), MMP-9 (gelatinase B) or MMP-12 (metalloelastase) on cellular fibrinolytic activity was studied with the use of smooth muscle cells (SMC) and fibroblasts derived from mice with specific inactivation of these genes. Activation of cell-bound plasminogen by two-chain urokinase-type plasminogen activator (tcu-PA) was not significantly different with SMC or fibroblasts from the gene-deficient mice (78% to 140% of wild-type). For all cell types, very limited conversion of plasminogen to angiostatin-like kringle-containing fragments was observed (< 3% of the total cell-bound plasminogen). Activation of plasminogen in solution by cell-associated tcu-PA was also comparable for SMC or fibroblasts of the different genotypes (54% to 160% of wild-type). In vitro SMC migration on scrape wounded collagen-coated surfaces was comparable for wild-type, MMP-7(-/-), MMP-9(-/-) and MMP-12(-/-) SMC, but was significantly reduced for MMP-3(-/-) SMC (P < .005 vs. wild-type). Serum-free conditioned medium of MMP-3(-/-) and MMP-7(-/-) SMC or fibroblasts induced similar lysis of fibrin films as wild-type cells. These findings indicate that several interactions that have been described between these MMPs and the plasminogen/plasmin system in a purified system do not significantly affect plasmin-mediated cellular fibrinolytic activity under cell culture conditions.
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PMID:Matrix metalloproteinase deficiencies do not impair cell-associated fibrinolytic activity. 1132 16

The integrin alpha v beta 6 is a fibronectin receptor that is undetectable on normal keratinocytes in situ, but is increased significantly in wound healing and in culture-established keratinocytes, suggesting that it may promote changes associated with cell motility. Using normal human oral keratinocytes we have shown that cultured cells express relatively high levels of alpha v beta 6 and this integrin has a functional role in both cell adhesion and migration towards fibronectin. We provide experimental evidence that the increased expression of alpha v beta 6 by normal human oral keratinocytes results in coordinate changes, which promote a more migratory phenotype. Thus increased expression of alpha v beta 6 results in a fibronectin-dependent increase in pro-matrix metalloproteinase 9, matrix metalloproteinase 9 activity increases normal human oral keratinocyte migration, and this may be further dependent on plasmin activation. The results suggest a key role for alpha v beta 6 in these processes and indicate a coordinated link between alpha v beta 6 expression and upregulation of matrix metalloproteinase 9. It appears that alpha v beta 6 may function in normal human oral keratinocyte migration through matrix-metalloproteinase-9-dependent and -independent mechanisms.
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PMID:alpha v beta 6 Integrin upregulates matrix metalloproteinase 9 and promotes migration of normal oral keratinocytes. 1140 78

Glycosylation influences the specific activities of serine proteases including tissue-type plasminogen activator and plasmin which act together in a ternary complex with fibrin. Serine proteases and matrix metalloproteinases (MMPs), including gelatinase B, participate in a protease cascade to remodel the extracellular matrix. In addition to the recognition and targeting functions of carbohydrates and the fact that they confer protease resistance on glycoproteins, oligosaccharides may extend particular protein domains of matrix remodelling enzymes and fine-control their activities within the context of the extracellular matrix. For example, the sialic acids of gelatinase B influence the catalytic activity of this enzyme in a complex with the tissue inhibitor of metalloproteinases-1 (TIMP-1).
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PMID:Matrix remodelling enzymes, the protease cascade and glycosylation. 1168 91

It is shown that the release of matrix metalloproteinase-9 (gelatinase B) by THP-1 and U937 cells into conditioned media is increased under the action of recombinant single-chain urokinase. This effect is not accompanied by proteolytic activation of gelatinase B and is related to release of a pro-form of the enzyme. The action of urokinase on monocytes is time-dependent and becomes significant 12-24 h after the beginning of cell incubation. The dependence of the effect on the concentration of urokinase is characterized by half-maximum at about 20 nM and saturation at about 200 nM. The urokinase-induced gelatinase B release is not dependent on the action of plasmin because plasmin inhibitors aprotinin and alpha2-antiplasmin do not abolish this action. Additionally, tissue type plasminogen activator does not induce gelatinase B release by monocytes as observed under the action of urokinase. Nevertheless, the catalytic activity of urokinase participates in the development of the observed effect because it is significantly depressed by the natural urokinase inhibitor PAI-1. The effect of urokinase is completely abolished by actinomycin D and cycloheximide, indicating the participation of transcription and translation processes in its development.
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PMID:Plasmin-independent gelatinase B (matrix metalloproteinase-9) release by monocytes under the influence of urokinase. 1170 74

Bovine pulmonary artery smooth muscle tissue possesses the tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) as revealed by immunoblot studies of the cytosolic fraction with polyclonal TIMP-1 antibody. In this report, we described the purification and partial characterization of the inhibitor from the cytosolic fraction of the smooth muscle. This inhibitor was purified by a series of anion-exchange, gel filtration and affinity chromatographic procedure. The purified inhibitor showed an apparent molecular mass of 30 kDa in SDS-PAGE. Amino terminal sequence analysis for the first 22 amino acids of the purified inhibitor was also found to be identical to bovine TIMP-1. This glycosylated inhibitor was found to be active against matrix metalloproteinase-9 (MMP-9, gelatinase B), the ambient matrix metalloproteinase in the pulmonary smooth muscle. The purified TIMP-1 was also found to be sensitive to pure rabbit and human fibroblast collagenase and type IV collagenase. In contrast, it had minimum inhibitory activity against bacterial collagenase. It was also found to be inactive against the serine proteases trypsin and plasmin. The inhibitor was heat and acid resistant and it had the sensitivity to trypsin degradation and reduction-alkylation.
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PMID:Identification, purification and partial characterization of tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) in bovine pulmonary artery smooth muscle. 1467 93

Fresh-frozen plasma (FFP) was evaluated for gelatinolytic and fibrinolytic activity. Gelatin zymography revealed that gelatinase A (MMP-2) was constitutively present in FFP whereas gelatinase B (MMP-9) was present at variable levels. The presence of MMP-9 likely represents differential release from neutrophils during FFP collection or processing. Although fibrin matrices generated from FFP or freshly prepared plasma contained characteristic crosslinked gamma-gamma dimers and beta-monomers, matrices generated from FFP were resistant to spontaneous plasmin-dependent fibrinolysis. This observation likely stems from the plasminogen activator instability and could potentially lead to a hypofibrinolytic state. The impact of these in vitro findings to protease balance in patients receiving multiple FFP doses remains to be determined.
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PMID:Gelatinolytic and fibrinolytic activity in fresh-frozen plasma. 1515 89

Extracellular proteolysis by the plasminogen/plasmin (Plg/plasmin) system and MMPs is required for tissue injury in autoimmune and inflammatory diseases. We demonstrate that a Plg cascade synergizes with MMP-9/gelatinase B in vivo during dermal-epidermal separation in an experimental model of bullous pemphigoid (BP), an autoimmune disease. BP was induced in mice by antibodies to the hemidesmosomal antigen BP180. Mice deficient in MMP-9 were resistant to experimental BP, while mice deficient in Plg and both tissue Plg activator (tPA) and urokinase Plg activator (uPA) showed delayed and less intense blister formation induced by antibodies to BP180. Plg-deficient mice reconstituted locally with Plg or the active form of MMP-9 (actMMP-9), but not the proenzyme form of MMP-9 (proMMP-9), developed BP. In contrast, proMMP-9 or actMMP-9, but not Plg, reconstituted susceptibility of MMP-9-deficient mice to the skin disease. In addition, MMP-3-deficient mice injected with pathogenic IgG developed the same degree of BP and expressed levels of actMMP-9 in the skin similar to those of WT controls. Thus, the Plg/plasmin system is epistatic to MMP-9 activation and subsequent dermal-epidermal separation in BP.
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PMID:Synergy between a plasminogen cascade and MMP-9 in autoimmune disease. 1584 Nov 69

Previous work has shown that endothelial cell (EC)-derived matrix metalloproteinases (MMPs) regulate regression of capillary tubes in vitro in a plasmin- and MMP-1 dependent manner. Here we report that a number of serine proteases can activate MMP-1 and cause capillary tube regression; namely plasma kallikrein, trypsin, neutrophil elastase, cathepsin G, tryptase and chymase. Plasma prekallikrein failed to induce regression without coactivators such as high molecular weight kininogen (HMWK) or coagulation Factor XII. The addition of trypsin, the neutrophil serine proteases (neutrophil elastase and cathepsin G) and the mast cell serine proteases (tryptase and chymase) each caused MMP-1 activation and collagen type I proteolysis, capillary tubular network collapse, regression and EC apoptosis. Capillary tube collapse is accompanied by collagen gel contraction, which is strongly related to the wound contraction that occurs during regression of granulation tissue in vivo. We also report that proMMP-10 protein expression is markedly induced in ECs undergoing capillary tube morphogenesis. Addition of each of the serine proteases described above led to activation of proMMP-10, which also correlated with MMP-1 activation and capillary tube regression. Treatment of ECs with MMP-1 or MMP-10 siRNA markedly delayed capillary tube regression, whereas gelatinase A (MMP-2), gelatinase B (MMP-9) and stromelysin-1 (MMP-3) siRNA-treated cells behaved in a similar manner to controls and regressed normally. Increased expression of MMP-1 or MMP-10 in ECs using recombinant adenoviral delivery markedly accelerated serine protease-induced capillary tube regression. ECs expressing increased levels of MMP-10 activated MMP-1 to a greater degree than control ECs. Thus, MMP-10-induced activation of MMP-1 correlated with tube regression and gel contraction. In summary, our work demonstrates that MMP-1 zymogen activation is mediated by multiple serine proteases and MMP-10, and that these events are central to EC-mediated collagen degradation and capillary tube regression in 3D collagen matrices.
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PMID:MMP-1 activation by serine proteases and MMP-10 induces human capillary tubular network collapse and regression in 3D collagen matrices. 1587 Jan 7

This study examined whether intraluminal thrombus in abdominal aortic aneurysms (AAAs) is a source of fibrinolytic activity and proteolysis that could weaken the aneurysm wall. Plasmin, tissue plasminogen activator (tPA), and urokinase plasminogen activator (uPA) activity, plasminogen activator inhibitor 1 (PAI-1), and alpha2-antiplasmin (alpha2AP) antigen were measured in the AAA wall and juxtamural and luminal aspects of intraluminal thrombus in 18 patients. The aneurysm wall contained 100-fold higher tPA activity (1.06 +/- 0.34 [standard error of measurement] U/mg soluble protein) compared with juxtamural thrombus (JMT) (0.011 +/- 0.001 ) and luminal thrombus (LT) (0.01 +/- 0.001) (p < .00001) and over 6-fold higher uPA activity (29.3 +/- 3.4 IU/mg compared with the JMT (4.3 +/- 2.4, p = .00024) and LT (7.9 +/- 1.76, p = .0005). The LT had significantly lower levels of PAI-1 (1.26 +/- 0.34 ng/mg) than the AAA wall (2.08 +/- 0.51, p = .04) and the JMT (3.94 +/- 0.85, p = .007). The levels of alpha2AP in the wall (19.4 +/- 3.1 ng/mg) were lower than in the JMT or LT (43.0 +/- 7.9 ng/mg, p = .013, and 47.6 +/- 6.0 ng/mg, p = .002, respectively). There was no significant difference, however, in plasmin activity among the AAA wall, JMT, and LT. There were significant amounts of latent gelatinase B (matrix metalloproteinase [MMP]-9) in the AAA, JMT, and LT. Mean levels of activated MMP-9 activity were similar in the AAA, JMT, and LT. Plasmin activation of MMPs at the interface between intraluminal thrombus and the aneurysm wall may enhance proteolysis and accelerate aneurysm expansion.
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PMID:Intraluminal thrombus enhances proteolysis in abdominal aortic aneurysms. 1684 17


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