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)

Decidual and placental relaxins have been proposed as autocrine/ paracrine hormones in the remodeling of collagen in the amnion and chorion in the last weeks of pregnancy. The matrix metalloproteinase-1 (MMP-1) is a key enzyme in the degradation of the interstitial collagens which predominate in the fetal membranes. Distribution of the MMP-1 gene and of the MMP-1 protein was shown by in situ hybridization and immunolocalization, respectively, in amnion, chorion, and decidua collected from patients before the onset of spontaneous labor. The distribution of MMP-1 in the chorionic cytotrophoblast and decidua coincided with that of the human relaxin receptor, detected by tissue section autoradiography in tissues collected at the same stage of pregnancy. Fetal membrane explants were used to study the effect of exogenous human relaxin H2. These responded by a dose-dependent increase in expression of the MMP-1 gene, in its secreted protein, and in its enzyme activity in the medium. A similar dose-dependent increase in the tissue plasminogen activator (tPA) gene and protein upon exposure of the explants to relaxin H2 suggested a coordinated cascade system, resulting in increases in secreted activities of MMP-1, MMP-3 (stromelysin), and MMP-9 (gelatinase B). There was no effect on the genes or proteins for MMP-2 (gelatinase A) or tissue inhibitor of metalloproteinase-1 (TIMP-1), showing the specificity of the response. This coordinated regulation by relaxin H2 of tPA, MMP-1, MMP-3, and MMP-9 would result in more complete degradation of the fetal membrane extracellular matrix components.
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PMID:An autocrine/paracrine role of human decidual relaxin. I. Interstitial collagenase (matrix metalloproteinase-1) and tissue plasminogen activator. 909 59

Stimulated monocytes are involved in blood clotting and fibrin dissolution by synthesizing tissue factor (TF) and fibrinolytic components such as plasminogen activator inhibitor type 2 (PAI-2). Heparin interacts with smooth muscle cells, platelets, and endothelial cells and specifically binds to human monocytes. In endothelial and smooth muscle cells, heparin selectively inhibits collagenase and tissue plasminogen activator gene expression. To investigate (1) heparin's influence on the hemostatic system by its interactions with plasma factors and cellular elements and (2) to determine its effects on gene expression in blood circulating cells, we studied the effect of heparin on TF and PAI-2 protein and mRNA in human lipopolysaccharide (LPS)- or interferon-gamma (IFN-gamma)-stimulated monocytes. TF and PAI-2 proteins were investigated by ELISA and by assaying procoagulant activity. The mRNA study was carried out by an initial PCR screening followed by a Northern blot semiquantitative analysis. Heparin (0.5 U/mL) inhibited both TF and PAI-2 production and gene expression. The contemporaneous protein and mRNA decrease (TF and PAI-2 protein 22 and 42%, respectively; suggests that this action is, at least partially, at the transcriptional level. The effect is not specific for heparin and is not demonstrated by other glycosaminoglycans (chondroitin-4-sulfate or dermatan sulfate). This action may be relevant for the antithrombotic activity of heparin in cell-mediated blood clotting activation.
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PMID:Tissue factor and plasminogen activator inhibitor type 2 expression in human stimulated monocytes is inhibited by heparin. 920 Mar 37

Exposure to zero gravity has been shown to cause a decrease in bone formation. This implicates osteoblasts as the gravity-sensing cell in bone. Osteoblasts also are known to produce neutral proteinases, including collagenase and tissue plasminogen activator (tPA), which are thought to be important in bone development and remodeling. The present study investigated the effects of zero gravity on development of calvariae and their expression of collagenase and tPA. After in utero exposure to zero gravity for 9 days on the NASA STS-70 space shuttle mission, the calvariae of rat pups were examined by immunohistochemistry for the presence and location of these two proteinases. The ages of the pups were from gestational day 20 (G20) to postnatal (PN) day 35. Both collagenase and tPA were found to be present at all ages examined, with the greatest amount of both proteinases present in the PN14 rats. At later ages, high amounts were maintained for tPA but collagenase decreased substantially between ages PN21 to PN35. The location of collagenase was found to be associated with bone-lining cells, osteoblasts, osteocytes, and in the matrix along cement lines. In contrast, tPA was associated with endothelial cells lining the blood vessels entering bone. The presence and developmental expression of these two proteinases appeared to be unaffected by the exposure to zero gravity. The calvarial thickness of the pups was also examined; again the exposure to zero gravity showed little to no effect on the growth of the calvariae. Notably, from G20 to PN14, calvarial thickness increased dramatically, reaching a plateau after this age. It was apparent that elevated collagenase expression correlated with rapid bone growth in the period from G20 to PN14. To conclude, collagenase and tPA are present during the development of rat calvariae. Despite being produced by the same cell in vitro, i.e., the osteoblast, they are located in distinctly different places in bone in vivo. Their presence, developmental expression, and quantity do not seem to be affected by a brief exposure to zero gravity in utero.
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PMID:Collagenase and tissue plasminogen activator production in developing rat calvariae: normal progression despite fetal exposure to microgravity. 979 27

The objective of this study was to establish a technique to isolate porcine mesothelial cells (PMCs) from omental tissue and to compare them to human mesothelial cells (HMCs). The PMCs were dispersed by collagenase digestion and isolated on a Ficoll layer. Their morphologic and ultrastructural features were assessed at confluence by light and electronic microscopy, and they were characterized by immunohistochemistry using specific HMC markers. PMC proliferation was studied in the presence of growth factors platelet-derived growth factor (PDGF), epidermal growth factor (EGF) or transforming growth factors beta1, beta2, or beta3 (TGF). Fibrinolytic PMC activity was detected by zymography for tissue plasminogen activator (tPA) and by reverse zymography for plasminogen activator inhibitor-1 (PAI-1). The recalcification time of cell lysates was used to define PMC procoagulant activity, and gelatinase zymography was used to detect metalloproteinase production. At confluence, PMCs formed typical cobblestone monolayers and exhibited structural features characteristic of HMCs. Weibel Palade bodies were never seen. Specific HMC markers (HBME1, ME1, WT1) cross-reacted with PMCs. As HMCs and PMCs coexpressed cytokeratin and vimentin, and also expressed vinculin and alpha-actin. Addition of PDGF or EGF to the culture medium stimulated PMC proliferation. PMCs constitutively expressed fibrinolytic and procoagulant activity and secreted MMP9 and MMP2. The technique described in this study allows isolation of mesothelial cells from porcine omental tissue. These porcine cells exhibit a mesothelial phenotype and functional properties similar to those of HMCs. Our data warrant an evaluation of mesothelial cells as targets in several therapeutic strategies with porcine models.
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PMID:Phenotypic and functional characteristics of porcine peritoneal mesothelial cells. 1061 73

Ligneous conjunctivitis (LC) is a rare disease of unknown etiology characterized by the growth of "woody" plaques on ocular and extraocular mucosa. These lesions are comprised of fibrin and both direct and indirect evidence implicates hypofibrinolysis as the primary defect in LC. To further elucidate the pathophysiology of LC we investigated the biochemical aspects of ligneous lesions with respect to the fibrinolytic system. Ligneous lesions were obtained from the right eye of a 15 year-old female patient with longstanding LC since age 2.5 year. Ligneous conjunctivitis in this patient has exhibited a chronic recurrent coarse and has involved multiple muscosal sites. Samples analyzed included an abundant mucoid thread from the conjunctival fornix and the ligneous plaque attached to the inferior tarsus. Samples were analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) to characterize protein profiles and by a variety of zymographic methods to visualize fibrinolytic enzymes. We found that mucoid and ligneous samples were distinct entities. Specifically, ligneous samples contained polypeptides with electrophoretic profiles characteristic of intact fibrin, and were replete in fibrin-bound tissue plasminogen activator (t-PA). Despite the presence of ample t-PA, ligneous samples were essentially devoid of fibrinolytic activity. In contrast, neither proteins nor t-PA could be detected in mucoid samples when fractionated by 7.5-15% SDS-PAGE or analyzed by fibrin zymography, respectively. Despite the absence of t-PA, mucoid samples were replete in fibrinolytic activity. This activity was plasminogen independent, heterogenous and inhibited by PMSF. Degradation profiles suggested that this activity represented in part alpha-chymotrypsin, consistent with this patient's treatment regime, as well as plasmin, elastase and an unidentified neutrophil-derived activity. Interestingly, ligneous samples contained both latent and activated forms of matrix metalloproteinase-9 (MMP-9), whereas mucoid samples contained predominantly activated forms of MMP-9. LC is characterized by defective fibrinolysis, despite the presence of ample t-PA and intact fibrin, and by an abundant mucoid thread which binds both endogenous and exogenous enzymes including serine protease(s) and collagenase(s). The implications of these results with respect to a role for exuberant mucus production or abnormal mucins in the development of a relative mucosal-site specific plasmin(ogen) deficiency is discussed.
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PMID:Ligneous conjunctivitis: biochemical evidence for hypofibrinolysis. 1070 63

Wound healing is a complex process involving the interactions of many different cell types, matrix components and biological factors, including proteinases and cytokines. This study compared the levels of proteinases (matrix metalloproteinases and plasminogen activators), proteinase inhibitors (tissue inhibitors of metalloproteinases and plasminogen activator inhibitors), inflammatory cytokines and growth factors in acute wound fluid samples collected from the surgical drains of elective breast (n = 24) and colorectal (n = 26) patients on the first postoperative day. Gelatin zymography was used to determine matrix metalloproteinase-2 and -9 levels, quenched fluorescence substrate hydrolysis was applied for total MMP activity and enzyme-linked immunoassays were used to quantitate other factors. Colorectal wound fluid samples showed significantly (p < 0.05) greater levels of the matrix metalloproteinases (MMP-1, 2, 3, and 9), tissue inhibitor of metalloproteinases-1, urokinase plasminogen activator receptor and the inflammatory cytokines (interleukin-1beta, -6, and tumor necrosis factor-alpha); e.g., matrix metalloproteinase-3 colon; median 275 (range 11-2.530) ng/ml; breast; 530-400. However, tissue plasminogen activator and growth factor levels (epidermal growth factor, platelet-derived growth factor, basic fibroblast growth factor, transforming growth factor-beta1) were significantly greater in breast samples; e.g., epidermal growth factor breast 468 (103-1, 444) pg/ml; colon 57(1-573). There was no difference in the levels of urokinase type plasminogen activator, plasminogen activator inhibitor-1 and -2, tissue inhibitor of metalloproteinases -2 or vascular endothelial growth factor. Acute wound fluid from different surgical wounds showed different profiles of proteinases, proteinase inhibitors, and cytokines. This may lead to differences in the rate of tissue remodeling and therefore healing in these two wounds in vivo.
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PMID:Proteinases, their inhibitors, and cytokine profiles in acute wound fluid. 1111 51

The aim of using enzymes in vitreoretinal surgery is to facility PVD and create pharmacological vitrectomy. It can be achieved by liquefying the gel structure of the vitreous (synchisis) and weakening of adherence of the posterior vitreous cortex to retina (syneresis). The article reviews currently used enzymes in vitreoretinal surgery (plasmin, hyaluronidase, dispase, chondroitinase, collagenase, urokinase, TPA--tissue plasminogen activator) and presents potential profits and side-effects related to their use. Although the day when vitreous surgery is replaced by pharmacological vitreolisis remains still as a future, these enzymes hold great promise. Additionally it has been proved that enzymes can be used successfully as an intraoperative adjuvant in vitrectomy.
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PMID:[Use of enzyme in vitreoretinal surgery]. 1204 13

Matrix metalloproteinase-14 is required for degradation of fibrillar collagen by mesenchymal cells. Here we show that keratinocytes use an alternative plasminogen and matrix metalloproteinase-13-dependent pathway for dissolution of collagen fibrils. Primary keratinocytes displayed an absolute requirement for serum to dissolve collagen. Dissolution of collagen was abolished in plasminogen-depleted serum and could be restored by the exogenous addition of plasminogen. Both plasminogen activator inhibitor-1 and tissue inhibitor of metalloproteinase blocked collagen dissolution, demonstrating the requirement of both plasminogen activation and matrix metalloproteinase activity for degradation. Cell surface plasmin activity was critical for the degradation process as aprotinin, but not alpha(2)-antiplasmin, prevented collagen dissolution. Keratinocytes with single deficiencies in either urokinase or tissue plasminogen activator retained the ability to dissolve collagen. However, collagen fibril dissolution was abolished in keratinocytes with a combined deficiency in both urokinase and tissue plasminogen activator. Combined, but not single, urokinase and tissue plasminogen activator deficiency also completely blocked the activation of the fibrillar collagenase, matrix metalloproteinase-13, by keratinocytes. The activation of matrix metalloproteinase-13 in normal keratinocytes was prevented by plasminogen activator inhibitor-1 and aprotinin but not by tissue inhibitor of metalloproteinase-1 and -2, suggesting that plasmin activates matrix metalloproteinase-13 directly. We propose that plasminogen activation facilitates keratinocyte-mediated collagen breakdown via the direct activation of matrix metalloproteinase-13 and possibly other fibrillar collagenases.
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PMID:Collagen dissolution by keratinocytes requires cell surface plasminogen activation and matrix metalloproteinase activity. 1219 5

We assessed the relative levels of secreted matrix metalloproteinases (MMPs) and plasminogen activators (PAs) in PC-3 cells, prostate fibroblasts and osteoblasts in the presence and absence of VEGF, TGF beta1 and bFGF. Fibroblasts and osteoblasts secreted more MMPs -1 and -2 than did PC-3 cells, while PC-3 s contributed the majority of PAs. MMP-1 expression was downregulated by transforming growth factor beta-1 (TGF beta1) treatment in prostate fibroblasts and upregulated by basic fibroblast growth factor (bFGF) in both stromal lines. In PC-3 cells, TGF beta1 and bFGF increased urokinase plasminogen activator secretion. TGF beta1 decreased tissue plasminogen activator secretion in all cell lines. Prostate cancer cells associated with fibroblasts or osteoblasts have a variety of MMPs and PAs to facilitate matrix degradation.
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PMID:Growth factor regulation of secreted matrix metalloproteinase and plasminogen activators in prostate cancer cells, normal prostate fibroblasts and normal osteoblasts. 1280 74

To minimize the neurotoxic injury by clot-derived substances after intracerebral hemorrhage (ICH) on the surrounding brain tissue, minimally invasive neurosurgical protocols have evolved evacuating the hematoma by stereotaxic injection of a fibrinolytic agent such as recombinant tissue plasminogen activator (rtPA), followed by aspiration of the lysed clot. However, the possible contribution of the presence of exogenous tPA itself to the toxic effects of hematoma-derived factors complicates the rationale and efficacy of this therapeutic approach. To clarify the role of exogenous rtPA on edema development, we examined the extent of edema formation in a murine model of collagenase-induced ICH, which included tPA-deficient (tPA-/-) and wild-type (wt) mice. In 16 (7 tPA-/- and 9 wt mice) out of 32 mice, 1 mg/kg rtPA was injected into the hematoma 5 h after ICH induction followed by aspiration of the liquefied clot 20 min later. In the control group (8 tPA-/- and 8 wt mice), only collagenase was injected. The edema volume was quantified using SPOT software on Luxol Fast Blue and Cresyl violet-stained cross-sections 24 h, 3, and 7 days post surgery. Twenty-four hours after ICH induction, tPA-/- mice had a significantly smaller edema volume (P< 0.01), even when rtPA was administered. Between days 3 and 7 after ICH, exogenous rtPA exerts its edema-promoting effect irrespective of the underlying genotype and exhibits an extensive microglial activation adjacent to the clot. In conclusion, the role of the endogenous tPA appears to be limited to the early phase of edema formation, whereas exogenous rtPA is edema-promoting between days 3 and 7 after ICH.
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PMID:The role of endogenous versus exogenous tPA on edema formation in murine ICH. 1529 33


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