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)

Keratocytes can become fibroblasts and myofibroblasts during corneal injury and wound healing. We used the in vitro bovine keratocyte repair model system, which involves culturing collagenase-isolated keratocytes in serum-free media and then adding serum or serum plus TGF-beta to the culture media to induce the fibroblast and myofibroblast phenotypes, respectively, to evaluate the synthesis of secreted products by the cells. Serum and serum plus TGF-beta rapidly induced the fibroblast morphology and alpha smooth muscle actin, a marker of myofibroblasts. Keratocytes cultured in serum and serum plus TGF-beta also increased the synthesis of several high molecular weight products (approximately 100kD and larger) and the accumulation of a 43kD protein shown to be osteonectin/SPARC by both sequencing tryptic peptides from the protein and by reaction with antisera to osteonectin/SPARC. Immunohistochemical staining of mouse corneas with antisera to SPARC seven days post-wounding also demonstrated an increased accumulation of SPARC in the regions undergoing repair. These results indicate SPARC accumulation is a marker for stromal repair.
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PMID:Increased SPARC accumulation during corneal repair. 1282 91

Hepatic fibrosis results from excess extracellular matrix produced primarily by hepatic stellate cells (HSC). In response to injury, HSC differentiate to a myofibroblastic phenotype expressing smooth muscle actin and fibrillar collagens. Relaxin is a polypeptide hormone shown to have antifibrotic effects in fibrosis models. In this study, activated HSC from rat liver were treated with relaxin to determine if relaxin can reverse markers of HSC activation. Relaxin treatment resulted in a decrease in the expression of smooth muscle actin, but had no effect on cell proliferation rate. The levels of total collagen and type I collagen were reduced, while the synthesis of new collagen was inhibited. Furthermore, relaxin caused an increase in the expression and secretion of rodent interstitial collagenase (MMP-13), but there was no effect on the gelatinases MMP-2 or MMP-9. Relaxin also increased secretion of TIMP-1 and TIMP-2. The effective concentration of relaxin to induce these effects was consistent with action through the relaxin receptor. In conclusion, relaxin reversed markers of the activated phenotype of HSC including the production of fibrillar collagen. At the same time, the activity of a fibrillar collagenase was increased. These data suggest that relaxin not only inhibits HSC properties that contribute to the progression of hepatic fibrosis, but also promotes the clearance of fibrillar collagen. Therefore, relaxin may be a useful approach in the treatment of hepatic fibrosis.
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PMID:Inhibition of markers of hepatic stellate cell activation by the hormone relaxin. 1294 68

Human cartilage is reported to contain multipotent stromal cells. We evaluated the effect of human cartilage-derived stromal cells (CDSCs) on heart function when transplanted into the infarcted myocardium of rats. CDSCs were isolated and cultured from human articular cartilage and subjected to fluorescence-activated cell sorting (FACS) analysis. The CDSCs were consistently negative for CD14, CD34, CD38, CD45, CD49f, CD104, CD105, CD106, CD117, HLA-DR, and ABCG-2, and positive for CD10, CD44, CD71, CD73, CD90, CD147, and HLA-A, -B, and -C by FACS analysis. Myocardial infarction (MI) was created in rats by ligation of the left anterior descending artery. Three weeks after MI, the CDSCs labeled with Hoechst stain were injected into the infarct and border zone. Echocardiography, histological examination, and reverse transcription-polymerase chain reaction (RT-PCR) were performed 4 weeks after cell transplantation. Echocardiography indicated that CDSC transplantation could improve heart function. The number of capillaries increased in the injection regions in the transplantation group. Histological examination showed that Hoechst-labeled CDSCs in islands within the infarcted region were stained positively for desmin and smooth muscle actin but negatively for alpha-sarcomeric actin and troponin-I. RT-PCR results indicated the expression level of collagen I, collagen III, tissue inhibitor of metalloproteinase-1, transforming growth factor-beta1, and vascular endothelia growth factor were much higher in the scar tissue in the transplantation group than in the medium and control groups. Our findings suggested that CDSCs might promote angiogenesis, prevent left ventricular remodeling, and improve the heart function when transplanted into injured heart in the rat model of myocardial infarction.
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PMID:Cartilage-derived stromal cells: is it a novel cell resource for cell therapy to regenerate infarcted myocardium? 1623 22

In the endotheliochorial placenta of the cat, the maternal surface epithelium and parts of the connective tissue have to be removed to bring the fetal blood vessels in close contact to the maternal capillaries. The composition of the extracellular matrix (ECM) in the feline uterus is not known and it is still not clear if and which parts of the maternal ECM persist during gestation in the placental labyrinth. We demonstrated various extracellular matrix components (collagen types I, III, IV, and laminin) and matrix metalloproteinases (MMP-1, -2, -13) using immunohistochemistry and studied the distribution of intermediate filaments (vimentin, cytokeratin) and alpha-smooth muscle actin (SMA) in the placental girdle on specimens of different stages of gestation. Collagen types I and III were mainly present in the fetal chorionic lamellae whereas diminished in the maternal placental labyrinth part. Collagen IV and laminin were expressed in fetal basement membranes and mesenchyme. Maternal endothelial cells and stromal cells showed a positive immunoreaction for anti-collagen type IV and laminin. MMP-2 was identified in the maternal stroma, including decidual cells. Endothelia of maternal blood vessels within the labyrinth contained MMP-1, -2 and -13, probably associated with angiogenesis. In the trophoblast MMP-1 and -13 were demonstrated. Maternal stem vessels were accompanied by a thick layer of syncytiotrophoblast. Around these vessels, collagen type I and SMA were present in a periendothelial region between the endothelium and the trophoblast. These findings indicate that a strictly regulated balance between ECM deposition and ECM degradation in the feline placental labyrinth is necessary for proper placental development and function.
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PMID:Extracellular matrix components and matrix degrading enzymes in the feline placenta during gestation. 1633 74

Intracellular IL-1 receptor antagonist (icIL-1ra) is reportedly involved in functions independent of blocking IL-1 receptor signaling. Fibroblasts derived from the involved skin of patients with systemic sclerosis (SSc) are predominantly of the myofibroblast phenotype, with higher levels of icIL-1ra compared to normal skin fibroblasts. We examined the effect of overexpression of icIL-1ra on the phenotype and function of normal fibroblasts with respect to the expression of alpha smooth muscle actin (alpha-SMA), a specific marker for myofibroblasts, and plasminogen activator inhibitor (PAI), a protein involved in fibrogenesis and expressed at higher levels in myofibroblasts, and the production of collagenase (matrix metalloproteinase-1 (MMP-1)), the major enzyme involved in the degradation of native collagen in the skin. Normal human foreskin fibroblasts overexpressing icIL-1ra showed higher levels of alpha-SMA and PAI and had lower levels of collagenase and MMP-1 mRNA induced by inflammatory cytokines. By contrast, levels of mRNA for tissue inhibitor of metalloproteinase-1 in the transfected cells were not different from the control cells. Pretreatment of the ic-IL-1ra-transfected cells with antisense oligonucleotide directed against the mRNA of icIL-1ra restored MMP-1 expression induced by stimulation with IL-1beta. Our data indicate novel functions for icIL-1ra, which might be relevant to the genesis of fibrotic diseases such as SSc.
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PMID:Novel functions of intracellular IL-1ra in human dermal fibroblasts: implications in the pathogenesis of fibrosis. 1645 36

Hepatic stellate cells (HSC) are located in Disse spaces of normal rat liver. In their quiescent state they serve as a storage site for vitamin A. In fibrotic liver they become activated, proliferate and they undergo transdifferentiation into myofibroblast-like cells. Changes in the cell phenotype are accompanied by changes in the cellular cytoskeleton. We have studied the expression of alpha-smooth muscle actin and intermediate filament proteins vimentin, desmin and glial fibrillary acidic protein (GFAP) by immunocytochemistry in HSC cultured for 2 or 7 days after isolation. Normal or cirrhotic rat liver was perfused with solutions of pronase and collagenase and HSC were isolated by density gradient centrifugation of the resulting cell suspension. Liver cirrhosis was produced in rats by repeated carbon tetrachloride administration. Vimentin was detected in all cells from normal and cirrhotic liver. The concentration of desmin in the cells from cirrhotic liver was slightly higher than that in normal cells and it increased with time in culture. GFAP could be detected only in normal cells 2 days after their isolation. In contrast, alpha smooth muscle actin (alpha-SMA) was absent from normal cells at this time but its expression was pronouced later. In most cells from cirrhotic liver this antigen was already present on the second day of culture and its expression further increased.
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PMID:Expression of cytoskeletal proteins in hepatic stellate cells isolated from normal and cirrhotic rat liver. 1664 26

The disease manifestations of schistosomiasis arise from the mammalian host-mediated type 2 T-helper cell-induced (Th2) fibro-granulomatous inflammatory response to eggs trapped within host tissues. Activated hepatic stellate cells are well described as the effector cells of hepatic fibrosis in a variety of human diseases and rodent models. The aim of this study was to further understand the mechanism of fibrosis and the role of hepatic stellate cells in hepatic schistosomiasis progression. Groups of female CBA mice, which produce an intermediate degree of Schistosoma japonicum-induced liver fibrosis, were infected with S. japonicum, perfused at fortnightly time points and the liver tissue and contained egg granulomas examined by immunohistochemistry and cytokine and chemokine analysis using quantitative PCR. Immunohistochemistry demonstrated the presence of activated hepatic stellate cells in the periphery of egg granulomas, adjacent to fibrotic areas. Time course analysis demonstrated that the transcription of smooth muscle actin-alpha type 1 collagen, IL-4, IL-13, IL-13Ralpha2 and tissue inhibitor of metalloproteinase-1 mirrored the initial increase and subsequent down-modulation of granuloma diameter in mice. However, the transcription of monocyte chemo-attractant protein-1, Regulated upon Activation Normal T Cell Expressed and Secreted (RANTES), TNF-alpha, IFN-gamma and matrix metalloproteinase-9 paralleled the evolution of the total liver disease burden. Transforming growth factor-beta1 transcription did not appear to be of biological significance in this mouse model. Immunohistochemical analysis of human hepatic granulomas showed close association of smooth muscle actin-alpha-expressing cells with fibrosis in five available cases of end-stage (advanced) schistosomiasis japonica. We conclude that activated hepatic stellate cells play a contributory role in the granulomatous, fibrotic process induced by S. japonicum eggs, both in the murine model and in human disease.
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PMID:A contributory role for activated hepatic stellate cells in the dynamics of Schistosoma japonicum egg-induced fibrosis. 1680 22

Biocompatibility and cell seeding capability of a new cell scaffold made of textured polylactic acid (PLA) fibers was investigated as a new material for tissue engineering of anterior cruciate ligaments (ACL). Adhesion and proliferation of human mesenchymal progenitor cells (MPC) was investigated after 15 days by scanning electron microscopy and standard histology. Expression of collagen type I and III, fibronectin, tenascin C, decorin, smooth muscle actin, and the matrix metalloproteinases MMP-1 and MMP-2, as well as their tissue inhibitors TIMP-1 and TIMP-2 was analyzed using real-time PCR. Protein expression of collagen I and III, tenascin C, and proliferating nuclear antigen (PCNA) was determined by immunohistology. Apoptosis was analyzed by detection of p53 expression and TUNEL staining. MPC seeded the scaffold homogeneously and showed good cell growth and no increased rate of apoptosis. After 15 days, the matrix forming genes collagen type I, tenascin C, and decorin were upregulated, indicating the formation of a ligament-like matrix. MMP-1 and TIMP-1 were also significantly increased, suggesting initial matrix remodeling. It was concluded that the new porous PLA scaffold allowed homogeneous cell seeding, a fibroblastic phenotype and the production of a ligament-like matrix and, therefore, might be a suitable cell carrier for ACL tissue engineering.
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PMID:Human mesenchymal progenitor cell responses to a novel textured poly(L-lactide) scaffold for ligament tissue engineering. 1692 14

Fibroblast activation protein (FAP), as described so far, is a type II cell surface serine protease expressed by fibroblastic cells in areas of active tissue remodelling such as tumour stroma or healing wounds. We investigated the expression of FAP by fibroblast-like synoviocytes (FLSs) and compared the synovial expression pattern in rheumatoid arthritis (RA) and osteoarthritis (OA) patients. Synovial tissue from diseased joints of 20 patients, 10 patients with refractory RA and 10 patients with end-stage OA, was collected during routine surgery. As a result, FLSs from intensively inflamed synovial tissues of refractory RA expressed FAP at high density. Moreover, FAP expression was co-localised with matrix metalloproteinases (MMP-1 and MMP-13) and CD44 splice variants v3 and v7/8 known to play a major role in the concert of extracellular matrix degradation. The pattern of signals appeared to constitute a characteristic feature of FLSs involved in rheumatoid arthritic joint-destructive processes. These FAP-expressing FLSs with a phenotype of smooth muscle actin-positive myofibroblasts were located in the lining layer of the synovium and differ distinctly from Thy-1-expressing and non-proliferating fibroblasts of the articular matrix. The intensity of FAP-specific staining in synovial tissue from patients with RA was found to be different when compared with end-stage OA. Because expression of FAP by RA FLSs has not been described before, the findings of this study highlight a novel element in cartilage and bone destruction of arthritic joints. Moreover, the specific expression pattern qualifies FAP as a therapeutic target for inhibiting the destructive potential of fibroblast-like synovial cells.
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PMID:Fibroblast activation protein is expressed by rheumatoid myofibroblast-like synoviocytes. 1710 46

The effect of halofuginone (Halo) on established fibrosis in older mdx dystrophic muscle was investigated. Mice (8 to 9 mo) treated with Halo (or saline in controls) for 5, 10, or 12 wk were assessed weekly for grip strength and voluntary running. Echocardiography was performed at 0, 5, and 10 wk. Respiratory function and exercise-induced muscle damage were tested. Heart, quadriceps, diaphragm, and tibialis anterior muscles were collected to study fibrosis, collagen I and III expression, collagen content using a novel collagenase-digestion method, and cell proliferation. Hepatocyte growth factor and alpha-smooth muscle actin proteins were assayed in quadriceps. Halo decreased fibrosis (diaphragm and quadriceps), collagen I and III expression, collagen protein, and smooth muscle actin content after 10 wk treatment. Muscle-cell proliferation increased at 5 wk, and hepatocyte growth factor increased by 10 wk treatment. Halo markedly improved both cardiac and respiratory function and reduced damage and improved recovery from exercise. The overall impact of established dystrophy and dysfunction in cardiac and skeletal muscles was reduced by Halo treatment. Marked improvements in vital-organ functions implicate Halo as a strong candidate drug to reduce morbidity and mortality in Duchenne muscular dystrophy.
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PMID:Functional resolution of fibrosis in mdx mouse dystrophic heart and skeletal muscle by halofuginone. 1831 May 7


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