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)

p38 mitogen-activated protein kinase (MAPK) regulates matrix metalloproteinase-1 (MMP-1) gene expression bidirectionally depending on the induction. We sought to determine whether cytokines related to the regulation of extracellular matrix could activate p38 MAPK in dermal fibroblasts. We determined p38 MAPK phosphorylation/activation in dermal fibroblasts stimulated with platelet-derived growth factor-BB (PDGF-BB), transforming growth factor-beta or interleukin-4. Induction of MMP-1 mRNA by PDGF-BB was enhanced in the presence of a specific inhibitor of p38 MAPK, suggesting that p38 MAPK would function as a negative regulator of the MMP-1 mRNA level. We then determined which isoforms of p38 MAPK expressed in dermal fibroblasts were responsible for the downregulation of the MMP-1 mRNA level. Overexpression of p38beta2, but not of p38alpha, significantly decreased PDGF-BB-induced MMP-1 promoter activity, although PDGF-BB activated signaling pathways to both p38alpha and p38beta2. Taken together, the results of this study indicate that p38beta2 can function as a negative regulator of MMP-1 induced by PDGF-BB in vitro, suggesting that activation of p38beta2 might contribute to the pathogenesis of cutaneous fibrosis.
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PMID:Activation of p38 MAPK suppresses matrix metalloproteinase-1 gene expression induced by platelet-derived growth factor. 1262 81

Ischemia-reperfusion (I/R) is thought to upregulate the expression and activity of matrix metalloproteinases (MMPs), which regulate myocardial and vascular remodeling. Previous studies have shown that transforming growth factor-beta(1) (TGF-beta(1)) can attenuate myocardial injury induced by I/R. TGF-beta(1) is also reported to suppress the release of MMPs. To study the modulation of MMP-1 by TGF-beta(1) in I/R myocardium, Sprague-Dawley rats were given saline and subjected to 1 h of myocardial ischemia [total left coronary artery (LCA) ligation] followed by 1 h of reperfusion (n = 9). Parallel groups of rats were pretreated with recombinant TGF-beta(1) (rTGF-beta(1), 1 mg/rat, n = 9) before reperfusion or exposure to sham I/R (control group). I/R caused myocardial necrosis and dysfunction, indicated by decreased first derivative of left ventricular pressure, mean arterial blood pressure, and heart rate (all P < 0.01 vs. sham-operated control group). Simultaneously, I/R upregulated MMP-1 (P < 0.01). Treatment of rats with rTGF-beta(1) reduced the extent of myocardial necrosis and dysfunction despite I/R (all P < 0.01). rTGF-beta(1) treatment also inhibited the upregulation of MMP-1 in the I/R myocardium (P < 0.05). To determine the direct effect of MMP-1 on the myocardium, isolated adult rat myocytes were treated with active MMP-1, which caused injury and death of cultured myocytes, measured as lactate dehydrogenase release and trypan blue staining, in a dose- and time-dependent manner (P < 0.05). Pretreatment with PD-166793, a specific MMP inhibitor, attenuated myocardial injury and death induced by active MMP-1. The present study for the first time shows that MMP-1 can directly cause myocyte injury or death and that attenuation of myocardial I/R injury by TGF-beta(1) may, at least partly, be mediated by the inhibition of upregulation of MMP-1.
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PMID:TGF-beta 1 attenuates myocardial ischemia-reperfusion injury via inhibition of upregulation of MMP-1. 1267 26

Connective tissue growth factor (CTGF) is a 38 Kda cysteine-rich, heparin-binding peptide that has been implicated in several normal and abnormal physiological processes. CTGF has been shown to be induced by transforming growth factor-beta. Previous studies in our pig model of skin wound healing showed a coordinate expression of transforming growth factor-beta and CTGF during the healing process. To better understand the function of CTGF during wound healing, normal porcine fibroblasts were isolated from skin samples from SPF Yorkshire pigs. At fourth passage the cells were cultured in Dulbecco's modified Eagle's medium supplemented with fetal calf serum and at 80% confluence the medium was replaced with supplemented serum-free medium. After a further 24 hours, cells were treated with 0, 10, 25, 50, 100, and 500 ng/ml of 38 Kda or 16-20 Kda (C-terminal truncated form) recombinant expressed human CTGF for 24 hours or treated with 100 ng/ml for 0, 12, 24, and 48 hours. Subsequently, CTGF effects on cell DNA synthesis and mRNA levels for a subset of relevant molecules were assessed. The results showed that in cells treated with 38 Kda rhCTGF, mRNA levels for types I and III collagen, fibromodulin, and basic fibroblast growth factor were significantly up-regulated, but mRNA levels for HSP47, decorin, biglycan, and versican were not significantly altered. mRNA levels for CTGF were also significantly increased, indicating autoregulation of expression. However, mRNA levels for transforming growth factor-beta, inteleukins 1 and 6, tumor necrosis factor-alpha, and nerve growth factor did not change. Interestingly, mRNA levels for the tissue inhibitors of metalloproteinase-1, -2, -3 and -4 were observed to significantly increase, but in contrast, mRNA levels for matrix metalloproteinases-1, -2, -9 were not significantly altered by exposure of the cells to the 38 Kda form of CTGF. In addition, DNA synthesis was augmented in the presence of 38 Kda rhCTGF. However, the truncated 16-20 Kda form of rhCTGF appeared to have none of these effects on porcine fibroblasts. These results indicate that in order to induce changes in porcine fibroblasts a molecule with an intact C-terminal domain is required, and that CTGF regulates porcine fibroblast extracellular matrix molecule, growth factor, and proteinase inhibitor gene expression without apparently affecting matrix metalloproteinase mRNA levels. These findings suggest that CTGF contributes to the anabolic environment during skin wound healing via selective modulation of fibroblast proliferation and changes to gene expression.
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PMID:Recombinant connective tissue growth factor modulates porcine skin fibroblast gene expression. 1275 4

In this study, we examined the sequential expression of several matrix metalloproteinases (MMPs), tissue inhibitors of metalloproteinases (TIMPs), and growth factors as well as the presence of apoptosis in a model of pulmonary fibrosis induced in rats with paraquat and hyperoxia. Animals showing neither clinical nor morphological changes with this double aggression were classified as "resistant". Rats were killed at 1, 2, 3, and 6 wk, and lungs were used for collagen content, gene expression by real-time PCR, gelatinolytic activity by zymography, apoptosis by in situ DNA fragmentation, and protein localization by immunohistochemistry. Our results showed a significant decrease of collagenases MMP-8 and MMP-13, with an increase of TIMP-1 and transforming growth factor-beta. Immunoreactive TIMP-1 was increased in experimental rats and primarily localized in alveolar macrophages. Expression of gelatinases MMP-2 and MMP-9 mRNAs was not affected, but lung zymography revealed an increase in progelatinase B, progelatinase A, and its active form. Epithelial apoptosis was evident from the first week, whereas at later periods, interstitial cell apoptosis was also noticed. Resistant animals behave as controls. These findings suggest that an imbalance between collagenases and TIMPs, excessive gelatinolytic activity, and epithelial apoptosis participate in the fibrotic response in this experimental model.
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PMID:Unbalanced collagenases/TIMP-1 expression and epithelial apoptosis in experimental lung fibrosis. 1288 63

Renal artery stenosis (RAS) may lead to renal injury, partly mediated through increased oxidative stress. However, the potential effects of chronic oral antioxidant intervention on the stenotic kidney remain unknown. This study was designed to test the hypothesis that chronic antioxidant vitamin supplementation in RAS would preserve renal function and structure. Single-kidney hemodynamics and function were quantified in vivo in pigs using electron-beam CT after 12 weeks of unilateral RAS (n=7), a similar degree of RAS orally supplemented with vitamins C (1 g) and E (100 IU/kg) (RAS+Vitamins, n=7), or controls (normal, n=7). Renal tissue was studied ex vivo using Western blotting and immunohistochemistry. Mean arterial pressure was similarly elevated in both RAS groups, while ischemic renal volume and glomerular filtration rate were similarly reduced. Renal blood flow was decreased in RAS compared with normal (326.5+/-99.9 versus 553.4+/-48.7 mL/min, respectively, P=0.01), but preserved in RAS+Vitamins (485.2+/-104.1 mL/min, P=0.3 versus normal). The marked increase in the expression of the NADPH-oxidase subunits p47phox and p67phox, nitrotyrosine, endothelial and inducible nitric oxide synthase, and nuclear factor-kappaB observed in RAS (P<0.05 versus normal) was normalized in RAS+Vitamins (P>0.1). Furthermore, trichrome staining and the expression of transforming growth factor-beta and tissue inhibitor of matrix-metalloproteinase-1 were also decreased in RAS+Vitamins. In conclusion, chronic blockade of the oxidative stress pathway in RAS using antioxidant vitamins improved renal hemodynamics and decreased oxidative stress, inflammation, and fibrosis in the ischemic kidney. These observations underscore the involvement of oxidative stress in renal injury in RAS and support a role for antioxidant vitamins in preserving the ischemic kidney.
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PMID:Beneficial effects of antioxidant vitamins on the stenotic kidney. 1292 65

CITED2 (CBP/p300-interacting transactivator with ED-rich tail 2) is a member of the Cited family of nuclear regulators, previously known as mrg1 (melanocyte-specific gene-related gene 1). CITED2 is inducible by varying stimuli including lipopolysaccharide, hypoxia, and cytokines such as interleukin 9 and interferon gamma. Using the immortalized human chondrocyte cell line, C-28/I2, we investigated whether CITED2 could be responsive to mechanical stimuli, and if so, whether CITED2 could mediate shear-driven regulation of matrix metalloproteinase (MMP) genes. The C-28/I2 cells were cultured under flow shear at 1-20 dyn/cm2, and the role of CIT-ED2 in regulation of MMPs was examined using the plasmids encoding sense and antisense CITED2 DNA sequences. The results showed that flow shear at 5 dyn/cm2 increased CITED2 mRNA and protein levels and down-regulated MMP-1 and MMP-13 mRNA and protein levels as well as enzyme activities. Consistent with the coordinated expression patterns of CITED2 and MMPs, overexpression of CITED2 repressed MMP-1 and MMP-13 mRNA levels and activities, whereas antisense CITED2 plasmids prevented the shear-induced down-regulation of MMP expression. Interleukin-1beta induced the formation of p300-Ets-1 complexes without affecting expression of CITED2. Transforming growth factor-beta as well as flow shear at 5 dyn/cm2 stimulated not only the expression of CITED2 but also the association of CIT-ED2 with p300 by dissociating Ets-1 from p300. These results indicate that CITED2 plays a major role in shear-induced down-regulation of MMP-1 and MMP-13 via a transforming growth factor-beta-dependent pathway.
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PMID:CITED2-mediated regulation of MMP-1 and MMP-13 in human chondrocytes under flow shear. 1296 Jan 75

The fibrous cap of a lipid-containing atherosclerotic plaque consists of collagen produced by arterial smooth muscle cells (SMCs) of synthetic phenotype. A thick cap protects the lipid-rich core, whereas a thin cap predisposes it to rupture, with ensuing acute clinical complications, such as myocardial infarction. Among the pathological mechanisms leading to plaque weakening and rupture, one possibility is loss of the matrix-synthesizing SMCs. Indeed, caps of ruptured coronary plaques contain a reduced number of SMCs. In contrast, in such lesions, the number of activated inflammatory cells, such as mast cells, is increased, suggesting that they may regulate the SMC number. We have shown that heparin proteoglycans secreted by activated mast cells can efficiently inhibit proliferation of SMCs in vitro and reduce their ability to produce collagen. Chymase, a neutral serine protease secreted by activated mast cells, can also inhibit SMC-mediated collagen synthesis by a transforming growth factor-beta-dependent and -independent mechanism, and moreover, cause degradation of the collagen matrix by activating latent interstitial collagenase (MMP-1). Furthermore, chymase can induce SMC apoptosis by degrading the extracellular matrix component fibronectin necessary for SMC adhesion, with subsequent disruption of focal adhesions and loss of outside-in survival signaling. Thus, activated mast cells may participate in the weakening and rupture of atherosclerotic plaques by secreting mediators, such as heparin proteoglycans and chymase, which affect the growth, function and death of arterial SMCs.
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PMID:Regulation of smooth muscle cell growth, function and death in vitro by activated mast cells--a potential mechanism for the weakening and rupture of atherosclerotic plaques. 1455 26

Matrix metalloproteinases (MMPs) degrade extracellular matrix components, and overexpression of these enzymes contributes to tissue destruction in arthritis. Of particular importance are the collagenases, MMP-1 and MMP-13, which have high activity against the interstitial collagens in cartilage. In this study, we address the mechanisms of two inhibitors of collagenase gene expression, the synthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO) and 15-deoxy-delta(12,14)-prostaglandin J2 (15-dPGJ2). Although both inhibitors are ligands for the nuclear hormone receptor peroxisome proliferator-activated receptor-gamma (PPAR-gamma), a connection between PPAR-gamma and collagenase gene expression has yet to be established. Here, we test the hypothesis that CDDO and 15-dPGJ2 use PPAR-gamma to repress MMP gene expression. Our findings with the PPAR-gamma antagonist 2-[4-[2-[3-(2,4-difluorophenyl)-1-heptylureido]ethyl]rsqb]-phenylsulfanyl]-2-methylpropionic acid (GW9662) and mouse embryonic fibroblasts lacking PPAR-gamma demonstrate that CDDO and 15-dPGJ2 use PPAR-gamma-independent mechanisms to inhibit collagenase gene expression. To address a potential PPAR-gamma-independent mechanism leading to the repression of MMPs by CDDO, we tested the effect of CDDO on the transforming growth factor-beta (TGF-beta) signaling pathway. We found that CDDO requires Smads (transcription factors activated by TGF-beta) for the repression of MMP-1. Specifically, MMP-1 is inhibited neither by CDDO in the absence of TGF-beta receptor-activated Smad3 nor when a negative regulator, Smad7, attenuates TGF-beta signaling. We conclude that CDDO represses MMP gene expression through a novel PPAR-gamma-independent mechanism that requires Smad signaling.
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PMID:Peroxisome proliferator-activated receptor-gamma-independent repression of collagenase gene expression by 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid and prostaglandin 15-deoxy-delta(12,14) J2: a role for Smad signaling. 1474 72

Asthma is a chronic inflammatory disease characterized by profound extracellular matrix changes referred to as bronchial remodelling. In this study, we evaluated matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs) mRNA expression in bronchial secretions of asthmatics and correlated MMPs modulations with the lung function as a reflection of the bronchial extracellular matrix remodelling. Quantitative RT-PCR was performed on cell pellets obtained from induced sputum in order to detect the mRNAs for MMP-1, -2, -3, -8, -9, -12, -13 TIMP-1, -2, while semiquantitative RT-PCR was performed to assess the expression of MMP-7, monocyte chemoattractant protein-1 (MCP-1) and transforming growth factor-beta(1) (TGF-beta(1)). The mRNA transcripts for MMP-1, TIMP-1 and monocyte chemoattractant protein-1 (MCP-1) were increased in cell pellets of induced sputum from asthmatics when compared to controls (P<0.05), and the intensity of MMP-1 mRNA expression inversely correlated with the FEV(1) in asthmatics (r=-0.49, P<0.05). The MMP-1 mRNA/TIMP-1 mRNA ratio correlated with the levels of MCP-1 mRNA in asthmatics (r=0.47, P<0.05). There were no differences between the groups with respect to mRNA coding for MMP-2, -3, -7, -8, -9, -12, -13, -14, TIMP-2 and TGF-beta(1). We conclude that cells contained in the bronchial secretions from asthmatics express higher amounts of mRNA for MMP-1 and TIMP-1, perhaps related to an increased expression of MCP-1, which might contribute to the extracellular matrix changes observed during airway remodelling.
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PMID:Matrix metalloproteinases and tissue inhibitors of matrix metalloproteinases mRNA transcripts in the bronchial secretions of asthmatics. 1496 24

Osteopontin is a multifunctional matricellular protein abundantly expressed during inflammation and repair. Osteopontin deficiency is associated with abnormal wound repair characterized by aberrant collagen fibrillogenesis in the heart and skin. Recent gene microarray studies found that osteopontin is abundantly expressed in both human and mouse lung fibrosis. Macrophages and T cells are known to be major sources of osteopontin. During lung fibrosis, however, osteopontin expression continues to increase when inflammation has receded, suggesting alternative sources of ostepontin during this response. In this study, we demonstrate immunoreactivity for osteopontin in lung epithelial and inflammatory cells in human usual interstitial pneumonitis and murine bleomycin-induced lung fibrosis. After treatment with bleomycin, osteopontin-null mice develop lung fibrosis characterized by dilated distal air spaces and reduced type I collagen expression compared with wild-type controls. There is also a significant decrease in levels of active transforming growth factor-beta(1) and matrix metalloproteinase-2 in osteopontin null mice. Type III collagen expression and total collagenase activity are similar in both groups. These results demonstrate that osteopontin expression is associated with important fibrogenic signals in the lung and that the epithelium may be an important source of osteopontin during lung fibrosis.
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PMID:Altered bleomycin-induced lung fibrosis in osteopontin-deficient mice. 1497 30


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