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)

Mouse oncostatin M (mOSM) has been recently cloned; however, its full spectrum of biologic functions has not been defined. To assess its potential role in inflammation, we have tested the activity of mOSM in vitro in regulation of fibroblasts and hepatic cells. At concentrations of 10 and 20 ng/ml, mOSM stimulates tissue inhibitor of metalloproteinase-1 (TIMP-1) mRNA in NIH-3T3 mouse embryonic fibroblasts, rat lung fibroblasts, and rat synovial fibroblasts, whereas mouse cardiotrophin-1 (mCT-1) or human OSM (hOSM) did not. Similarly, only mOSM was able to induce transcription of chloramphenicol acetyl-transferase (CAT) in NIH-3T3 cells transfected with a minimal TIMP-1 promoter/CAT construct. Mouse OSM had strong action inducing primary rat hepatocyte cultures to produce acute phase proteins; however, mOSM was very weak in its ability to stimulate acute phase protein synthesis in rat H35 cells or human HepG2 cells, which was consistent with weak STAT activation in H35 cells and HepG2 cells. Binding studies showed that NIH-3T3 cells possessed high affinity binding sites for mOSM, but rat H35 cells did not. On the other hand, mCT-1 and mouse IL-6 induced strong STAT activation as well as marked increases in acute phase protein production by H35 cells. These results indicate that mOSM does not share a functional receptor with mCT-1 or hOSM in mouse and rat cells and that hOSM does not activate the putatively specific OSM receptor on mouse or rat cells. These results also suggest that mOSM is an important cytokine in inflammation, through modulation of fibroblast function as well as hepatocyte responses.
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PMID:Regulation of tissue inhibitor of metalloproteinase-1 in fibroblasts and acute phase proteins in hepatocytes in vitro by mouse oncostatin M, cardiotrophin-1, and IL-6. 927 35

Oncostatin M (OSM) is a multifunctional cytokine, a member of the interleukin-6/leukemia inhibitory factor (IL-6/LIF) family, that can regulate a number of connective-tissue cell types in vitro including cartilage and synovial tissue-derived fibroblasts, however its role in joint inflammation in vivo is not clear. We have analyzed murine OSM (muOSM) activity in vitro and in vivo in mouse joint tissue, to determine the potential role of this cytokine in local joint inflammation and pathology. The effects of muOSM and other IL-6/LIF cytokines on mouse synovial fibroblast cultures were assessed in vitro and showed induction of monocyte chemotactic protein-1, interleukin-6, and tissue inhibitor metalloproteinase-1, as well as enhancement of colony growth in soft agarose culture. Other IL-6/LIF cytokines including IL-6, LIF, or cardiotrophin-1, did not have such effects when tested at relatively high concentrations (20 ng/ml). To assess effects of muOSM in articular joints in vivo, we used recombinant adenovirus expressing muOSM cDNA (AdmuOSM) and injected purified recombinant virus (10(6) to 10(8) pfu) intra-articularly into the knees of various mouse strains. Histological analysis revealed dramatic alterations in the synovium but not in synovium of knees treated with the control virus Ad-dl70 or knees treated with Adm-IL-6 encoding biologically active murine IL-6. AdmuOSM effects were characterized by increases in the synovial cell proliferation, infiltration of mononuclear cells, and increases in extracellular matrix deposition that were evident at day 4, but much more marked at days 7, 14, and 21 after administration. The synovium took on characteristics similar to pannus and appeared to contact and invade cartilage. Collectively, these results provide good evidence that OSM regulates synovial fibroblast function differently than other IL-6-type cytokines, and can induce a proliferative invasive phenotype of synovium in vivo in mice on overexpression. We suggest that OSM may contribute to pathology in arthritis.
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PMID:Murine oncostatin M stimulates mouse synovial fibroblasts in vitro and induces inflammation and destruction in mouse joints in vivo. 1102 23

There is ample evidence supporting the view that alterations in the balance between matrix deposition and matrix degradation brought about by changes in the respective activities of matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinases (TIMPs) contribute significantly to cardiac dysfunction and disease. Here we show that TIMP-1 was upregulated up to threefold after treatment with the inflammatory mediator and gp130 ligand oncostatin M (OSM) in human adult cardiac myocytes and fibroblasts. The Erk1/2 inhibitor PD98059 and the p38 inhibitor SD202190 abolished the effect of OSM on TIMP-1 production in both cell types. Human cardiac myocytes and human cardiac fibroblasts also express MMP-1, 2, 3 and 9, and TIMP-2 constitutively. OSM, however, did not affect the expression of these proteins. In addition also the other gp130 ligands tested, cardiotrophin-1 (CT-1), interleukin-6 (IL-6) and leukemia inhibitory factor (LIF) had no effect on the expression of TIMPs and MMPs studied. We speculate that OSM by inducing TIMP-1 expression counteracts excessive proteolysis and unrestricted matrix degradation during inflammatory processes in the heart. The notion that OSM favors matrix stabilization in the human heart is further supported by our earlier observation that OSM also upregulates PAI-1, the physiological inhibitor of the protease urokinase-type PA (u-PA), which in turn is essential for extracellular proteolysis. Therefore we propose a role for the gp130 ligand OSM in the modulation of cardiac remodeling and repair processes.
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PMID:The gp130 ligand oncostatin M regulates tissue inhibitor of metalloproteinases-1 through ERK1/2 and p38 in human adult cardiac myocytes and in human adult cardiac fibroblasts: a possible role for the gp130/gp130 ligand system in the modulation of extracellular matrix degradation in the human heart. 1589 Mar 57

Rupture of an atherosclerotic plaque is a key event in the development of cardiovascular disorders, in which matrix metalloproteinase-1 (MMP-1) plays a crucial role by degradation of extracellular matrix resulting in plaque instability. Cardiotrophin-1 (CT-1), a member of interleukin-6-type proinflammatory cytokines, has potent cardiovascular actions and is highly expressed in vascular endothelium, however its role in atherosclerosis has not been fully elucidated to date. The present study was designed to investigate whether CT-1 induces MMP-1 in human aortic endothelial cells (HAECs). Ribonuclease protection assay demonstrated that MMP-1 gene level in HAECs was enhanced by the treatment of CT-1 in a dose- and time-dependent manner. Immunocytochemical staining, Western immunoblot analysis and enzyme-linked immunosorbent assay revealed that CT-1 augmented MMP-1 protein synthesis and secretion. MMP-1 activity assay revealed that MMP-1 present in the supernatant of HAECs was exclusively precursor form. Casein zymography disclosed proteolytic activity in the supernatant of HAECs, which was enhanced by CT-1 treatment. Furthermore, pharmacological inhibitor study indicated the important roles of extracellular signal-regulated kinase (ERK) 1/2, p38 mitogen-activated protein (MAP) kinase, c-Jun N-terminal kinase (JNK) and Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling pathways in mediating CT-1-induced MMP-1 gene and protein expression. These data reveal for the first time that CT-1 induces the proteolytic potential in HAECs by upregulating MMP-1 expression through ERK1/2, p38 MAP kinase, JNK and JAK/STAT pathways, and suggest that CT-1 may play an important role in the pathophysiology of atherosclerosis and plaque instability.
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PMID:Cardiotrophin-1 induces matrix metalloproteinase-1 in human aortic endothelial cells. 2393 88