Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.3 (collagenase)
 18,340 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A leupeptin analogue, pyroglutamyl-Leu-Arg-CHO (Pyr-Leu-Arg-CHO), is an inhibitor of urokinase and plasmin, while leupeptin inhibits only plasmin. Pyr-Leu-Arg-CHO was shown to inhibit in vitro invasion of human fibrosarcoma HT1080 cells reducing cellular collagenase activity. Pyr-Leu-Arg-CHO suppressed the invasion of the cells in a Boyden chamber assay with an IC50 of 12 micrograms/ml. Addition of plasminogen to HT1080 cells increased the type IV collagenase activity, and Pyr-Leu-Arg-CHO inhibited this activation of the collagenase with an IC50 of 3 micrograms/ml. Leupeptin inhibited both the invasion and collagenase activation at higher concentrations than that of Pyr-Leu-Arg-CHO. The gelatin zymography of the conditioned medium revealed that a new gelatinolytic band, possibly an activated form of MMP-2, appeared by the addition of plasminogen. The activation of MMP-2 was also inhibited strongly by Pyr-Leu-Arg-CHO. These results indicate that Pyr-Leu-Arg-CHO suppresses the in vitro invasion by preventing the activation of type IV collagenase through inhibition of the urokinase-plasmin system.
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PMID:Suppression of in vitro invasion of human fibrosarcoma cells by a leupeptin analogue inhibiting the urokinase-plasmin system. 772 42

Many bacteria that spread in the skin produce enzymes that digest extracellular matrix components. Borrelia burgdorferi spreads from a skin inoculation site to form the characteristic erythema migrans skin lesion. It was determined that B. burgdorferi does not produce collagenase, elastase, hyaluronidase, or other enzymes that digest extracellular matrix components. However, B. burgdorferi bound human plasmin, plasminogen (Pgn), and urokinase-type plasminogen activator (uPA). When spirochetes were sequentially incubated with Pgn and uPA, bioactive plasmin was generated on the surface of B. burgdorferi. B. burgdorferi did not produce an endogenous Pgn activator. Fluorochrome-conjugated uPA and Pgn colocalized to the terminus of the spirochete. In a mouse model, uPA-treated B. burgdorferi were more infectious than control spirochetes. Binding of host uPA and Pgn to form a bioactive extracellular matrix protease on B. burgdorferi represents a mechanism that could facilitate dissemination and localization of spirochetes to sites of vascular injury.
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PMID:Binding of human plasminogen and urokinase-type plasminogen activator to the Lyme disease spirochete, Borrelia burgdorferi. 775 1

Evidence indicates that breakdown of articular cartilage resulting in the loss of normal joint function is the distinctive feature of osteoarthritis. Degradation of cartilage extracellular matrix components involves the action of at least 2 classes of proteinases: serine proteinases and metalloproteinases. Receptors have been described on a wide range of cell lines for many such proteinases [urokinase-type plasminogen activator (u-PA), plasminogen/plasmin, collagenase], which subsequently activate each other on the solid phase of the cell surface, leading to cartilage destruction. We review the leading role of u-PA and its receptor (u-PAR) in cartilage degradation.
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PMID:Plasminogen activator and receptor in osteoarthritis. 775 14

Inflammatory bone resorption, a characteristic feature of periodontal disease and rheumatoid arthritis, appears to be mediated by interleukin-1 beta (IL-1 beta). IL-1 beta has been shown to stimulate a wide range of proteolytic enzymes, including collagenases and plasminogen activators, in particular chondrocytes, synovial cells, and isolated osteoblasts. In this study, we have examined the hypothesis that IL-1 beta may stimulate bone loss by inducing the activity of plasminogen activators (PAs) in bone cultures. The latter would convert plasminogen to plasmin, which in turn can activate precursor procollagenase to collagenase. Active collagenase would then break down the bone collagen matrix. In the present study, release of 45Ca from fetal rat long bones in culture was studied in the presence of plasminogen and IL-1 beta. Plasminogen and IL-1 beta separately enhance resorption of fetal rat long bones in vitro. When plasminogen and IL-1 beta are added together at suboptimal levels, mainly additive effects are observed. The presence of heat-inactivated serum does not alter these results. These data tend to indicate that IL-1 beta is stimulating bone resorption through both PA-dependent and PA-independent pathways.
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PMID:Effects of plasminogen and interleukin-1 beta on bone resorption in vitro. 784 4

Inflammatory cytokines like interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-alpha) are linked to abnormal cartilage and bone loss in a variety of pathological conditions. We have investigated the effect of TNF-alpha on the synthesis and/or steady-state mRNA levels of collagen, alkaline phosphatase (ALP), plasminogen activators (PAs) and their inhibitor PAI-1, and collagenases (MMPs) and their inhibitor TIMP-1 by human osteoblastic, HOS TE85, cells in monolayer cultures. HOS TE85 cells possess approximately 2000 TNF-alpha receptors per cell with a Kd value of 0.67 nM and receptor of approximately 60 kDa. TNF-alpha enhances urokinase-plasminogen activator (u-PA) activity and steady-state mRNA levels twofold without affecting tissue-plasminogen activator (t-PA) or PAI-1. The increase in u-PA mRNA is due to enhanced transcription of this gene. mRNA levels or activities of collagenase 1 (MMP-1), 72- and 92-kDa gelatinases (MMP-2 and MMP-9) are also nearly doubled with little change in the level of expression of TIMP-1. TNF-alpha does not significantly affect the activity or mRNA levels of ALP. TNF-alpha decreases collagen as well as general protein synthesis. However, the steady-state mRNA for the alpha 2 chain of collagen type I is increased three- to fourfold. These results show that TNF-alpha may increase pathological bone turnover by enhancing the rate of transcription of proteases capable of degrading the nonmineralized osteoid layer and decelerating the maturation of the extracellular matrix formed by osteoblasts.
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PMID:Modulation of proteases and their inhibitors in immortal human osteoblast-like cells by tumor necrosis factor-alpha in vitro. 808 23

The neutral protease, plasmin, is generated by plasminogen activators, and is ascribed an important role in several physiological and pathological circumstances characterized by tissue remodelling and cell motility. The two types of plasminogen activator, tissue-type (tPA) and urokinase-type (uPA), are produced by osteoblasts, as is the specific PA inhibitor, PAI-1. Some hormones which activate bone resorption increase PA activity produced by osteoblasts, by decreasing the production of PAI-1. The increased PA activity has been suggested to facilitate bone resorption by activating latent collagenase, thus preparing the bone surface for osteoclastic resorption. Targeted and regulated production of plasmin might also contribute to the coupling of bone formation to resorption, by activating latent TGF beta in bone, and activating IGF-1 by freeing it from association with inhibitory binding protein. TGF beta itself is a powerful inhibitor of PA activity, an effect achieved by enhancing mRNA and protein for PAI-1. Thus the PA system is a potentially important regulatory system in bone remodelling, whose local activity is controlled through concerted actions of hormones and locally generated growth factors and cytokines.
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PMID:The plasminogen activator and inhibitor system in bone remodelling. 813 Jul 29

Atherosclerosis is an inflammatory reaction to accumulated extracellular lipid in the arterial intima. Evidence from pathological studies indicate that there is constant deposition and lysis of fibrin within the atherosclerotic arterial wall. In patients with stable peripheral atherosclerosis, the functional severity of the disease is associated with circulating fibrinogen and degradation of cross-linked fibrin reflecting procoagulant activity in the blood-vessel wall interface, or in the wall itself. In atheromas the fibrinolytic activity is connected to macrophages, which can assemble in the plasminogen-plasmin system and generate plasmin-mediated pericellular proteolysis in tissues with inflammation. Plasmin capable of activating collagenase may therefore be a candidate for plaque rupture. The nature of the exposed vascular tissue, the inflammatory state, tissue-factor dependent thrombin generation and the degree of matrix degradation regulate platelet reactivity. Little is yet known about platelet adhesive functions in proteolyzed collagens that are the underlying substrate where platelets deposit during plaque rupture, the triggering event for thrombosis. Research in these areas is likely to improve the understanding of the thrombogenicity of atheromas when the tissue is suddenly exposed to blood.
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PMID:Inflammation in atheroma: implications for plaque rupture and platelet-collagen interaction. 813 97

Radiation-induced damage in the central nervous system (CNS) is believed to be targeted to glial or endothelial cells or both, although the pathophysiology of the process is still poorly understood. In this study, we irradiated rat astrocytes with single doses of X-rays and then estimated the levels of tissue plasminogen activator (tPA) and collagenase in serum-free medium and cell extracts at different times. Fibrin zymography revealed increased levels of intracellular tPA activity at 12 hr after irradiation. Gelatin zymography showed continuously increasing levels of extracellular 72-kDa type-IV collagenase after irradiation. Quantitative enzymatic activities by densitometry showed a 3- to 4-fold elevation in the level of the intracellular tPA activity at 12 hr and a 5- to 6-fold increase in the level of the extracellular 72-kDa type-IV collagenase activity at 48 hr. An ELISA with specific antibodies for tPA and 72-kDa type-IV collagenase indicated a 5-fold increase in the level of tPA at 12 hr and a more-than-7-fold increase in the level of 72-kDa type-IV collagenase at 48 hr. This study adds considerable credibility to the proposed role of plasminogen activators and type-IV collagenase in the development of CNS damage after radiotherapy for brain tumors.
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PMID:Induction of tissue-type plasminogen activator and 72-kDa type-IV collagenase by ionizing radiation in rat astrocytes. 831 4

Current hypotheses suggest that the degradation of cervical collagen and elastin leads to cervical effacement and dilation during labor. The collagenolytic activity is thought to be initiated through the conversion of latent (pro)collagenase to active collagenase by the plasmin formed from plasminogen or by other proteases similarly formed from their inactive zymogens. We presently demonstrate that meperidine stimulates the activity of several enzymes in the proteolytic cascade leading toward proteolysis of connective tissue proteins. Meperidine in its therapeutic concentration range produces a 26% stimulation of urokinase activity on substrate S-2444, a 39% stimulation of plasmin activity on substrate S-2551, and a 33% stimulation of collagenase activity on 14C-labeled globin substrate. These direct effects on the enzyme activities are noted in vitro with the purified enzymes and were confirmed with several small molecular weight chromogenic substrates and with 14C-globin protein substrate. Oxytocin at levels found during active labor fails to stimulate the in vitro activity of purified urokinase, plasmin, collagenase, trypsin, or tissue-type plasminogen activator. The effect of meperidine on the proteolytic enzymes suggests that its ability to promote cervical effacement and distention during labor may be at least partially due to a meperidine-induced stimulation of cervical proteases.
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PMID:Direct stimulation of urokinase, plasmin, and collagenase by meperidine: a possible mechanism for the ability of meperidine to enhance cervical effacement and dilation. 847 75

Plasmin and matrix metalloproteinases (MMPs) both participate in extracellular matrix remodeling. This study examined the effects of tumor necrosis factor-alpha (TNF-alpha) and plasminogen on collagenase, stromelysin, and plasminogen activator inhibitor-1 (PAI-1) synthesis of collagenase and stromelysin, which remained predominantly in proenzyme forms, as determined by Western analysis of culture media. In contrast, plasminogen and plasmin not only increased secretion of MMPs but also induced cleavage to their active forms. The serine protease inhibitor aprotinin inhibited this activation of MMPs by plasminogen and plasmin. TNF-alpha reduced plasminogen-induced activation of MMPs, suggesting induction of an inhibitor or plasmin generation, such as PAI-1. Enzyme-linked immunosorbent assay of culture media showed that TNF-alpha (10 ng/mL) increased PAI-1 secretion by 4.2 fold compared with control (105.5 +/- 9.6) versus 24.9 +/- 1.7 ng/mL, n = 3). Surprisingly plasminogen also increased PAI-1 secretion by vascular SMCs (3.6-fold over control). These results demonstrate coordination of cytokines and serine proteases in regulating MMP secretion and activation. In addition, the induction of PAI-1 by TNF-alpha and plasminogen suggests a negative feedback mechanisms limit both plasmin-mediated and MMP-mediated matrix degradation.
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PMID:Regulation of matrix metalloproteinases and plasminogen activator inhibitor-1 synthesis by plasminogen in cultured human vascular smooth muscle cells. 860 4


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