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)

Matrix metalloproteinases (MMPs) and their inhibitors are important in connective tissue re-modelling in diseases of the cardiovascular system, such as atherosclerosis. Various members of the MMP family have been shown to be expressed in atherosclerotic lesions, but MMP9 is consistently seen in inflammatory atherosclerotic lesions. MMP9 over-expression is implicated in the vascular re-modelling events preceding plaque rupture (the most common cause of acute myocardial infarction). Reduced MMP9 activity, either by genetic manipulation or through pharmacological intervention, has an impact on ventricular re-modelling following infarction. MMP9 activity may therefore represent a key mechanism in the pathogenesis of heart failure. We have determined the crystal structure, at 2.3 A resolution, of the catalytic domain of human MMP9 bound to a peptidic reverse hydroxamate inhibitor as well as the complex of the same inhibitor bound to an active-site mutant (E402Q) at 2.1 A resolution. MMP9 adopts the typical MMP fold. The catalytic centre is composed of the active-site zinc ion, co-ordinated by three histidine residues (401, 405 and 411) and the essential glutamic acid residue (402). The main differences between the catalytic domains of various MMPs occur in the S1' subsite or selectivity pocket. The S1' specificity site in MMP9 is perhaps best described as a tunnel leading toward solvent, as in MMP2 and MMP13, as opposed to the smaller pocket found in fibroblast collagenase and matrilysin. The present structure enables us to aid the design of potent and specific inhibitors for this important cardiovascular disease target.
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PMID:Crystal structure of human MMP9 in complex with a reverse hydroxamate inhibitor. 1205 44

Dense collagen matrices obtained by using the property of type I collagen to form liquid crystals at high concentrations, were shown to be colonized by human dermal fibroblasts (Biomaterials 23 (2002) 27). In order to evaluate them as possible tissue substitutes, we investigated in this study the mechanism of cell colonization. Fibroblasts were seeded at the surface of collagen matrices at concentrations of 5 and 40 b mg/ml. Cell density and migration were estimated from histological sections over 28 days within 500 microm thick matrices. At day 14, migration started in the 40 mg/ml matrices, attaining 320 microm in distance and 5500 cell/mm(3) in density at day 28. As zymography and western blot techniques demonstrated production of collagenase 1 (MMP1) and gelatinase A (MMP2) in culture medium, collagen hydrolysis was required for cells to penetrate the collagen network. Furthermore, the presence of MMP1 and MMP2 and their tissue inhibitors TIMP1 and TIMP2 was revealed by immunohistochemistry. We presently show that 40 mg/ml collagen matrices are colonized by human dermal fibroblasts and reach, at day 28, a density close to that measured in human dermis.
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PMID:Fibroblast populated dense collagen matrices: cell migration, cell density and metalloproteinases expression. 1552 55

Pancreatic islet formation is a highly regulated process that is initiated at the end of gestation in rodents. Endocrine precursor cells first form within the epithelium of duct-like structures and then delaminate from the epithelium, migrate, and cluster during the early stages of islet formation. The molecular mechanisms that regulate endocrine cell migration and islet formation are not well understood. Cell culture studies suggest that matrix metalloproteinases (MMPs) 2 and 9 are required for islet formation. To address whether MMP2 and MMP9 function are essential for endocrine cell migration and islet formation in vivo, we analyzed pancreas development in MMP2/MMP9 double-deficient mice. Our results show that islet architecture and function are unperturbed in these knockout mice, demonstrating that both MMP2 and MMP9 functions are dispensable for islet formation and endocrine cell differentiation. Our studies also show that a number of other MMPs are expressed at the time islet formation is initiated. This observation suggests that other MMPs may substitute for MMP2 and MMP9 loss in pancreatic tissue. However, islet formation is unaffected in transgenic mice with modified tissue inhibitor of metalloproteinase-1 (TIMP1) levels, suggesting that MMP activity may contribute little to islet morphogenesis in vivo.
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PMID:Matrix metalloproteinases 2 and 9 are dispensable for pancreatic islet formation and function in vivo. 1573 45

The aim of this study was to validate the use of transcriptional profiling as a means of characterizing the complex interactions of the thousands of genes that are expressed during fracture healing. Standard mid-diaphyseal tibia fractures were generated in C57/B6 murine tibiae and the transcriptional expression of approximately 13,000 genes was assessed. Three time points after fracture were assessed: day 3, representative of the inflammatory phase; day 10, representative of the peak of cartilage formation; and day 21, representative of the period of primary bone formation and coupled remodeling. A self-organizing mapping approach of the data revealed the temporal relationships between the expression of mRNAs for extracellular matrix proteins and the proteases that degrade the proteoglycan and collagenous matrices. A broad group of extracellular matrix protein mRNAs representative of basement membranes, blood vessels and cartilage all showed elevated expression over the first 21 days of fracture healing. The sorting of the data identified an orderly temporal expression of the metalloproteinases and ADAMTS during the progression of fracture healing with (MMP2/MMP14/TIMP2) and ADAMTS4 and 15 preceding the expression of (MMP9/MMP13). Based on their patterns of expression, relative to the known activities of the encoded proteolytic enzymes, our results suggest that the dissolution of cartilage protoeglycans proceeds before the underlying collagenous components of the matrix are removed. The exclusion of several mRNAs that are normally expressed by osteoclasts in the profiles of mRNAs from days 3 and 10 suggests that osteoclastic activity was largely absent during the early periods of cartilage tissue formation and that proteoglycan and specific collagenase activities, precedes or is prerequisite to later osteoclast infiltration into the remodeling tissues.
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PMID:Analysis of fracture healing by large-scale transcriptional profile identified temporal relationships between metalloproteinase and ADAMTS mRNA expression. 1658 76

Bullous pemphigoid (BP) is an autoimmune subepidermal blistering disease which pathogenesis is associated with destruction of the basement membrane components and the anchoring fibers. The binding of autoantibodies to antigens localized in the basement membrane of the epidermis activates a series of immunological and enzymatic phenomena that lead to blister formation. There are some data that MMPs are involved in the development of skin lesions in BP, however their exact role in this process is not fully understood. We aimed to investigate whether MMPs and their inhibitors (TIMPs), assessed by their tissue expression, are involved in the pathogenesis of BP. The localization and expression of collagenase (MMP1), gelatinase (MMP2), 92 kD gelatinase (MMP9) and stromelysin 2 (MMP10) and TIMP1, 2, 3 were examined by immunohistochemistry in skin biopsies as well as in normal human skin specimens. The study included 21 patients with BP at an active stage of the disease. The MMPs and TIMPs serum levels were measured by ELISA method. Expression of MMP1, MMP2, MMP9 and MMP10 was observed either in the whole epidermis or in the basal keratinocytes. Most of the enzymes examined, apart from TIMP3, were detected in dermal part of the blister. Expression of the majority of the enzymes examined was observed in blister fluid however, the most intense signal was noted for MMP10. In cellular infiltrate we found expression of all the MMPs and TIMPs, the most distinct for MMP1, MMP2, MMP10 and for TIMP2. In all biopsies obtained from healthy volunteers only single basal keratinocytes gave positive, weak signal for the examined proteins. The MMPs and TIMPs serum levels in the control group were normal while in some cases of BP patients they were increased. Based on the results we conclude that imbalance between these enzymes really occurs in BP and it is likely to take important part in the pathogenesis of the disease.
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PMID:Disturbances of the expression of metalloproteinases and their tissue inhibitors cause destruction of the basement membrane in pemphigoid. 1701 68

Recessive inactivating mutations in human matrix metalloproteinase 2 (MMP2, gelatinase A) are associated with syndromes that include abnormal facial appearance, short stature, and severe bone loss. Mmp2(-/-) mice have only mild aspects of these abnormalities, suggesting that MMP2 function is redundant during skeletal development in the mouse. Here, we report that Mmp2(-/-) mice with additional mutations that render type I collagen resistant to collagenase-mediated cleavage to TC(A) and TC(B) fragments (Col1a1(r/r) mice) have severe developmental defects resembling those observed in MMP2-null humans. Composite Mmp2(-/-);Col1a1(r/r) mice were born in expected Mendelian ratios but were half the size of wild-type, Mmp2(-/-), and Col1a1(r/r) mice and failed to thrive. Furthermore, composite Mmp2(-/-);Col1a1(r/r) animals had very abnormal craniofacial features with shorter snouts, bulging skulls, incompletely developed calvarial bones and unclosed cranial sutures. In addition, trabecular bone mass was reduced concomitant with increased numbers of bone-resorbing osteoclasts and osteopenia. In vitro, MMP2 had a unique ability among the collagenolytic MMPs to degrade mutant collagen, offering a possible explanation for the genetic interaction between Mmp2 and Col1a1(r). Thus, because mutations in the type I collagen gene alter the phenotype of mice with null mutations in Mmp2, we conclude that type I collagen is an important modifier gene for Mmp2. Developmental Dynamics 236:1683-1693, 2007. (c) 2007 Wiley-Liss, Inc.
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PMID:Type I collagen is a genetic modifier of matrix metalloproteinase 2 in murine skeletal development. 1744 Sep 87

Incisional hernias represent one of the most common complications of laparotomies. Previous investigations have suggested that a disorder in collagen fiber structure and production level may be an important pathologic cause of abdominal wall hernias. We hypothesized that a cross-examination of multiple extracellular matrix biomarkers might identify underlying defects contributing to the development of hernias. We examined two patient populations: patients with incisional hernias (presenting for hernia repair) and patients with no hernia after previous laparotomy (undergoing a second laparotomy). Patients with previous wound infections, open abdomens, or on steroids were excluded. Fascia samples were obtained from all patients at the time of their second operation and they were studied. Western blots and reverse transcriptase-polymerase chain reaction were used to determine the ratio of type I, III, and IV collagens, as well as matrix metalloproteinase 1 (MMP1) and MMP2 in both groups. Values of P < 0.05 were considered statistically significant. At the protein level, collagen I/III ratio was slightly decreased in patients with incisional hernias compared with those with no hernia, whereas it was significantly decreased at the mRNA transcript level (0.49 vs 1.03, P < 0.01, respectively). The MMP-1 mRNA transcripts were not different in incisional hernia (IH) versus nonincisional hernia, but the MMP-2 level was significantly increased in patients with IH. Reduced collagen I/III and MMP-1/MMP-2 ratios in IH might be consequence of the biological activities between key elements participating in the development of IH after laparotomies. The potential role of MMP-2-specific inhibitors in preventing IH is of significance for future studies.
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PMID:Role of biomarkers in incisional hernias. 1765 92

The innate immune system mediates the initial inflammatory response that follows infection or injury. Although the innate immune response of fish to infection has been relatively well characterized during recent years at both cellular and molecular levels, no studies have examined the role of extracellular matrix (ECM) in the regulation of innate immunity and inflammation. We report here that collagen and gelatin in vitro were able to prime the respiratory burst of phagocytes from the bony fish gilthead seabream. In addition, collagen and gelatin induced a specific set of immune-related and ECM remodelling enzymes that substantially differed from that induced by pathogen-associated molecular patterns. Notably, both collagen and gelatin induced the expression of interleukin-1beta, chemokine (C-C motif) ligand 4 and matrix metalopeptidases (MMP) 9 and 13 in acidophilic granulocytes and macrophages but were unable to significantly increase the expression of other pro-inflammatory genes. Furthermore, it was found that the MMP2/MMP9 inhibitor V had a dose-dependent inhibitory effect on seabream phagocyte activation by either collagen or gelatin. In contrast, pre-treatment of collagen and gelatin by collagenase resulted in a higher stimulatory capacity compared to non-digested proteins. Collectively, these results indicate that collagen fragments produced by the action of different host proteases, and probably released by infectious agents, are sensed by fish phagocytes. Therefore, we propose that, besides to the well-established response to infection, the innate immune system of fish is able to respond to tissue injury.
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PMID:Collagen regulates the activation of professional phagocytes of the teleost fish gilthead seabream. 1918 48

Tumor necrosis factor (TNF) is an inflammatory cytokine that is upregulated in a number of cardiomyopathies. Adverse cardiac remodeling and dilation result from degradation of the extracellular matrix by matrix metalloproteinases (MMPs). We investigated whether TNF can directly trigger expression and activation of MMPs in cardiac cells. We compared MMP expression profile and activities between primary cultures of mouse neonatal cardiomyocytes and cardiofibroblasts and in cellular and extracellular compartments. In response to recombinant TNF (rTNF, 20 ng/ml), cardiomyocytes exhibited faster and more pronounced superoxide production compared with cardiofibroblasts, concomitant with increased expression of several MMPs. MMP9 levels increased more rapidly and about twofold more in cardiomyocytes than in cardiofibroblasts. TNF did not induce MMP2 expression. Expression of collagenases (MMP8, MMP12, MMP13, and MMP14) increased significantly, while total collagenase activity increased to a greater degree in conditioned medium of cardiomyocytes than in cardiofibroblasts. rTNF-mediated MMP expression and activation were dependent on superoxide production and were blocked by apocynin, an NADPH oxidase inhibitor. We identified phosphatidylinositol 3-kinase (PI3K)gamma as a key factor in TNF-mediated events since TNF-induced superoxide production, MMP expression, and activity were significantly suppressed in cardiomyocytes and cardiofibroblasts deficient in PI3Kgamma. We further demonstrated that the TNF-superoxide-MMP axis of events is in fact activated in heart disease in vivo. Wild-type and TNF(-/-) mice subjected to cardiac pressure overload revealed that TNF deficiency resulted in reduced superoxide levels, collagenase activities, PI3K activity, and fibrosis leading to attenuated cardiac dilation and dysfunction. Our study demonstrates that TNF triggers expression and activation of MMPs faster and stronger in cardiomyocytes than in cardiofibroblasts in a superoxide-dependent manner and via activation of PI3Kgamma, thereby contributing to adverse myocardial remodeling in disease.
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PMID:Tumor necrosis factor induces matrix metalloproteinases in cardiomyocytes and cardiofibroblasts differentially via superoxide production in a PI3Kgamma-dependent manner. 2000 53

We investigated the matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinase (TIMPs) proteins in transitional cell carcinoma (TCC) cell lines and surgical specimens of the bladder neoplasm. The expression level was correlated to the degree of cellular differentiation and invasiveness of bladder cancer. Panels of six TCC cell lines with different degrees of differentiation were tested with monoclonal antibodies (mAbs) to MMP-1, MMP-2, MMP-3, MMP-9a, MMP-9b, TIMP-1 and TIMP-2 by immunocytochemistry. Gelatin zymography was also conducted on the cell lines for MMP-2 and -9. In addition, immunohistochemistry with the mAbs to MMP and TIM molecules was performed on 30 TCC specimens. We found that TCC cell lines were stained positively for MMP-1 (6/6), weakly for MMP-9a (2/6), MMP9b (5/6) and TIMP-1 (3/6), and negatively for MMP-2 (3/6) and MMP-3 (3/6). Zymographic analysis of the cell lines showed a high level of MMP2 in the MGH-U4 cell line. In bladder cancer surgical specimens, all specimens were positive for MMP1 (30/30), 19 were positive for MMP-2 (63.3%), 21 positive for MMP-9a (70%) and 15 positive for MMP-9b (50%). The expression of MMP-2 was found to be positively correlated with higher-grade tumors (p=0.036) and the expression of MMP-9a and -9b was found to be positively correlated with tumor stage (p=0.012 and 0.023, respectively). However, the expression of MMP-1, MMP-3, TIMP-1 and TIMP-2 was not correlated with either tumor staging or grading. In conclusion, the expression of MMP-2 and -9 was correlated with high-grade or high-stage bladder tumors, respectively. However, this correlation was not observed with TCC cell lines in which high- and low-grade tumors are included. Immunohistochemical results on tumor lesions may have more clinical relevance, since in a given tumor microenvironment the interaction among tumor cells in situ and tumor-associated cells, such as neutrophils, macrophages, lymphocytes and endothelial cells, as well as environmental factors (hypoxia and pH), cytokines and growth factors released by these cells may be required for TCC to express selective MMPs and TIMPs. The selective expression of these molecules then regulates tumor progression.
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PMID:Profiling of matrix metalloproteinases and tissue inhibitors of metalloproteinases proteins in bladder urothelial carcinoma. 2296 65


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