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)

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

Wound healing is critical for survival. The damaged tissue is usually replaced by connective tissue, which forms permanent scar. This causes the impairment of organ function. The scar is the effect of synthesis and degradation of extracellular matrix. Many factors are involved in the process of wound healing, among them growth factors: TGF-beta and PDGF and proteolytic enzymes such as elastase and collagenase. Further studies for the mechanisms leading to scar formation, factors that play role in this process and interactions among them could provide basis for the therapeutic modification and outcome of wound healing.
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PMID:[Mechanisms of tissue repair]. 1523 Jan 5

Monocyte migration is one of the key events occurring in the early stage of atherosclerosis. This process includes monocytic adhesion to and penetration through the arterial intima. In such an environment, many factors stimulate the monocytes to enhance integrin activation and extracellular matrix degradation. To investigate the coordinative operation of these two events in relation to monocyte migration, we paid particular attention to the effects of granulocyte-macrophage colony-stimulating factor (GM-CSF) on monocytes in terms of RhoA activation and matrix metalloproteinase (MMP) expression. RhoA and integrin clustering were activated by GM-CSF, monocyte chemoattractant protein-1 (MCP-1) and platelet-derived growth factor-BB (PDGF-BB) in human monocytic cell lines. Furthermore, enhancement of migration was observed with stimulation by MCP-1 and PDGF-BB. Granulocyte-macrophage colony-stimulating factor did not enhance the migration, even though it activated RhoA and integrin. However, GM-CSF is known to stimulate monocytes to express MCP-1, suggesting the presence of an indirect mechanism for GM-CSF-mediated migratory activity. In contrast, only GM-CSF enhanced the expression of MMP-1 and MMP-9. These results provide evidence that GM-CSF has multiple functions enhancing monocytic migration via RhoA and integrin activation, and via MMP expression.
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PMID:GM-CSF activates RhoA, integrin and MMP expression in human monocytic cells. 1536 38

Migration of adventitial fibroblasts contributes to vascular remodeling after angioplasty. This study has used perivascular gene transfer of a truncated platelet-derived growth factor PDGF receptor (PDGFXR) to investigate whether antagonism of PDGF signaling alters adventitial cell migration after balloon injury in rat carotid arteries. Adenoviruses coordinating expression of beta-galactosidase (LacZ) and PDGFXR or LacZ and green fluorescent protein (GFP) were applied to the perivascular surface of arteries and balloon injury performed 4 days later. Vessels were excised at 3, 7, and 14 days to determine morphology and gene expression. Uninjured arteries only expressed LacZ positive cells in the adventitial compartment; however, after injury in LacZ and GFP transfected arteries, LacZ positive cells contributed to the population of cells within the media and neointima at 7-14 days. Overexpression of PDGFXR and LacZ resulted in a significant reduction in the number of LacZ labeled cells in the neointima after vascular injury, concomitant with reduced remodeling, collagen content, expression of matrix metalloproteinase-2, and increased levels of tissue inhibitors of metalloproteinase-1 and -2. We provide evidence that perivascular antagonism of PDGF attenuates remodeling and contribution of adventitial fibroblasts to neointima formation after balloon angioplasty. Perivascular gene transfer may represent a therapeutic strategy to reduce the incidence of restenosis.
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PMID:Antagonism of platelet-derived growth factor by perivascular gene transfer attenuates adventitial cell migration after vascular injury: new tricks for old dogs? 1679 May 26

Previous work has shown the importance of tumour-stroma interactions for prostate cancer development at the primary site. The aim of the present study was to find out whether evidence can be found for a tumour-stroma cross- talk also between metastatic prostate cancer cell lines and non-prostatic stromal fibroblasts which are encountered by metastatic cells at most sites. We addressed this issue in cell culture systems using 3 metastatic human prostate cancer cell lines (LnCaP, PC-3 and DU-145) on the one hand, and a human fibroblast line (HFF, human foreskin fibroblasts) on the other. We incubated fibroblasts with tumour cell- and tumour cells with fibroblast-conditioned media and evaluated several parameters important for the establishment of metastases such as cell proliferation, migration and expression of matrix degrading proteases. We also determined in the conditioned media the concentrations of several growth factors and cytokines which might be responsible for the observed effects. We found that media conditioned by all 3 metastatic prostate cancer cell lines stimulated fibroblast proliferation which corresponds to fibrous stroma induction in vivo. DU-145 cell conditioned media induced in fibroblasts expression of mmp-1 mRNA known to be important for tumour invasion. ELISA assays revealed that tumour cells secrete bFGF, PDGF and TNFalpha known to stimulate fibroblast proliferation and/or MMP-1 expression. Cultivation of DU-145 carcinoma cells in fibroblast conditioned medium resulted in an enhanced proliferation and anchorage-independent growth of this cell line in soft agar. Fibroblast conditioned medium also increased migration of PC-3 cells in the wound assay and slightly augmented mmp-1 expression. KGF (able to stimulate proliferation of normal and neoplastic prostate epithelial cells) was secreted by fibroblasts at higher concentrations than by all 3 tumour cell lines. In addition, fibroblasts secreted TNFalpha, bFGF, PDGF, HGF and also VEGF, the most important factor for tumour vascularization. Our results provide evidence that tumour-stroma interactions do not only exist at the primary site but also between metastatic prostate cancer cell lines and their fibroblastic microenvironment. These interactions, which are mediated through secreted factors, affect several steps of the metastatic cascade including proliferation, anchorage-independent growth, migration and the secretion of matrix-degrading proteases.
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PMID:Tumour-stroma interactions between metastatic prostate cancer cells and fibroblasts. 1701 25

A new 3D porous and biostable collagen scaffold has been developed to improve the biocompatibility of implantable glucose sensors by minimizing tissue reactions while stimulating angiogenesis around the sensors. The novel collagen scaffold was crosslinked using nordihydroguaiaretic acid (NDGA) to enhance biostability. NDGA-treated collagen scaffolds were stable without physical deformation in the subcutaneous tissue of rats for 4 weeks. In contrast, glutaraldehyde (GA)-treated collagen scaffolds were extremely damaged following implantation. Both types of scaffolds (NDGA- and GA-crosslinked) were stable in vitro in the presence of collagenase with 70% retention of original weight after 4 weeks of incubation. The response current (i.e. sensitivity) of sensors with porous scaffolds was not significantly changed when compared with control sensors (no scaffold), while the response time (T(95%)) was slightly delayed after a glucose concentration increase from 5 to 15 mM. Above this range, the sensors coated with scaffolds had only a slightly lower sensitivity than the control sensors. These results indicate that we have developed a stable NDGA-crosslinked collagen scaffold for biosensors, and that the scaffold does not impair the function of our sensor. We plan to use this scaffold to enhance the function and lifetime of the implantable biosensors by providing a controlled local environment around the sensors with the help of various drugs and growth factors (dexamethasone, VEGF, PDGF).
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PMID:A novel porous collagen scaffold around an implantable biosensor for improving biocompatibility. I. In vitro/in vivo stability of the scaffold and in vitro sensitivity of the glucose sensor with scaffold. 1808 51

Long term loosening of hip prostheses remains an important problem in orthopedics. Although various loosening mechanisms have been proposed, the exact process is still unclear. Particle disease and the pressure theory are widely known and generally accepted hypotheses to explain long term implant failure. Each proposed mechanism recognizes a local inflammatory response in which macrophages represent the main cell-type and several proinflammatory and antiinflammatory cytokines (IL-1beta, IL-6, TNFalpha, IL-10, TGFbeta), chemokines (IL-8/CXCL8, MCP-1/CCL2, RANTES/CCL5, MIP-1alpha/CCL3) and other mediators (GM-CSF, M-CSF, MMP-1, PDGF-alpha, PGE(2), IL-11) are identified. The cytokines have different functions and some are capable of stimulating bone resorption in various ways; either directly or indirectly. Even though the implant loosening is thought to be "aseptic", several studies suggested a possible role for bacteria and a bacterial biofilm in implant failure. Biofilm-derived bacteria and bacterial products might have an underestimated and potential role in the loosening process. In this article we will discuss the possible role of a bacterial biofilm and the importance of the local surrounding environment in "aseptic" loosening of hip prostheses.
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PMID:The local inflammatory environment and microorganisms in "aseptic" loosening of hip prostheses. 1809

Chlorotyrosine is an oxidative product of hypochlorous acid and l-tyrosine, and is considered as a biomarker for oxidative stress and cardiovascular disease. However, it is not clear whether chlorotyrosine could directly contribute to vascular pathogenesis. In this study, we investigated the effect and potential mechanisms of chlorotyrosine on human aortic smooth muscle cell (AoSMC) migration. With Boyden chamber and wound healing assays, chlorotyrosine significantly increased AoSMC migration in a concentration- and time-dependent manner. In addition, chlorotyrosine significantly increased the expression of several key molecules related to cell migration including PDGF receptor-B (PDGFR-B), matrix metalloproteinases (MMP-1 and MMP-2) and integrins (alpha3, alphaV, and beta3) in AoSMC at both mRNA and protein levels. Furthermore, chlorotyrosine also increased superoxide anion generation in AoSMC with the fluorescent dye dihydroethidium (DHE) staining. Activation of mitogen-activated protein kinases (MAPKs) was analyzed with Bio-Plex Luminex immunoassay and Western blotting. Chlorotyrosine induced a transient phosphorylation of ERK1/2, but not JNK and p38 MAPKs. Antioxidants including selenomethionine (SeMet) and Mn(III) tetrakis (4-benzoic acid) porphyrin (MnTBAP) as well as ERK1/2 inhibitor PD98059 effectively blocked chlorotyrosine-induced AoSMC migration. Thus, these findings demonstrate new biological functions of chlorotyrosine in human SMC migration, which may play a crucial role in the vascular lesion formation.
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PMID:Chlorotyrosine promotes human aortic smooth muscle cell migration through increasing superoxide anion production and ERK1/2 activation. 1828 Oct 51

Objective. To examine new investigative biomarkers and their relevance for radiographic severity in knee osteoarthritis. Methods. The group comprised 63 patients with 73 knees examined. Patients were divided according to radiographic severity to allow for comparison of biomarker levels. Hyaluronic acid (HA), matrix metalloproteases (MMP-1, MMP-3 and MMP-13), tissue inhibitors of metalloproteases (TIMP-1 and TIMP-2), platelet-derived growth factor (PDGF-AB), transformed growth factor (TGF-beta), vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF) and insulin-like growth factor (IGF-I) were measured on synovial fluid and in plasma releasate at a single time point. Principal component analysis (PCA) followed by analysis of covariance were applied to evaluate data. Results. Four different groups of biomarker were identified in plasma releasates. The first (platelet number, PDGF-AB and TGF-beta) and second groups (HA and IGF-I) were related to radiographic severity, P = .005 and P = .022, respectively. The third (MMP-1 and TIMP-2) and fourth groups (MMP-3 and TIMP-1) represented the catabolic balance, but were not associated to radiographic grading. Three different clusters of biomarkers were found in synovial fluid but did not show any significant association to radiographic grading. Conclusions. New imaging approaches to assess structural deterioration and correlation with biomarker levels are warranted to advance in OA research.
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PMID:Relationship between Investigative Biomarkers and Radiographic Grading in Patients with Knee Osteoarthritis. 2013 Aug 1

The aim of the investigation was to study the specific features of morphological manifestations and the molecular bases of lung tissue remodeling in progressive idiopathic pulmonary fibrosis (IPF). The investigation used open and transbronchial biopsy specimens from 110 patients with IPE/idiopathic pneumonia syndrome in 1997 to 2008. Immunohistochemical analysis was carried out on serial paraffin-embedded lung tissue slices from 20 patients with IPF and 20 control patients. Immunohistochemical staining for the detection of antigens in the paraffin-embedded slices was made using the antibodies to MMP-1, MMP-2, MMP-7, TIMP-4, Apo-CAS, PCNA, PDGF, EGFR, CD34, and SMA. Nonparametric statistical methods were employed. Our findings have indicated that in early-stage IPF, there are proliferating myofibroblasts in the myofibroblastic foci, mainly in the bronchioloalveolar transitional zone (BATZ), which express PCNA and PDGF. Both in early- and late-stage IPF, there were signs of increased readiness of the alveolar and bronchiolar epithelium of BATZ for apoptosis, as judged from Apo-CAS expression. At the same time no Apo-CAS expression was recorded in the myofibroblasts. In the early stage of the disease, the expression of MMP-1, MMP-2, MMP-7, and TIMP-4 in the epitheliocytes, macrophages, fibroblasts, and myofibroblasts was higher than that in the late stage of IPF. At the same time, late-stage IPF was characterized by the higher expression in all lung tissue cells than was early-stage IPF. There was also a significant increase in vessel density in both early and late stages of IPF as compared with intact lung tissue particularly in the BATZ in the control group. Thus, lung tissue remodeling in the progression of IPF from the early to late stage of the disease comprises interrelated processes that are largely localized in the BATZ, such as immune inflammation with pathological reparation, neoangiogenesis, apoptosis, and proliferation of epitheliocytes and myofibroblasts, which lead to the development of interstitial fibrosis and adenomatosis of the lung.
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PMID:[The mechanism of lung tissue remodeling in the progression of idiopathic pulmonary fibrosis]. 2108 35


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