Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.24.35 (matrix metalloproteinase 9)
 2,207 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mesangial cells are known to secrete metalloproteinases that are capable of degrading the constituents of the GBM, and hence are potentially involved not only in the regular maintenance of the ECM components in the glomerulus, but also of contributing to any damage to these components that occurs in disease states. In this report we positively identify by Northern blotting the neutral proteinase that is constitutively secreted by the human mesangial cell (HMC) as gelatinase A (MMP2). Stimulation of HMC gelatinase by IL-1 beta or PMA causes an increase in the total amount of gelatinolytic activity secreted. On examination, however, this increased activity is shown, both by immunoreactivity and by PCR to be due to the induction of the higher molecular weight form of gelatinase, gelatinase B (MMP9), while the amount of gelatinase A remained unaffected. In addition antigen and messenger RNA have been identified for both the specific inhibitors of metalloproteinases TIMP-1 and TIMP-2. The appearance of the larger inducible gelatinase with similar substrate specificity implies that the regular turnover of matrix components may be due to the constitutively released gelatinase A while in pathological situations the inducible gelatinase B becomes predominant. The synthesis and secretion of TIMP-1 and TIMP-2 indicates that the mesangial cell is capable of controlling the activity of its own secreted enzymes.
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PMID:Identification and independent regulation of human mesangial cell metalloproteinases. 799 10

We previously reported that murine tumor cells with a high spontaneous metastatic potential to the lung secrete higher amounts of M(r) 95,000 gelatinase (matrix metalloproteinase 9, MMP9) than do poorly metastatic cells. The present study, conducted to clarify the mechanisms underlying the increase in MMP9, revealed an autocrine factor that enhances the secretion of M(r) 95,000 gelatinase (MMP9). The secretion of MMP9 by highly metastatic colon carcinoma LuM1 cells, detected by zymography, was augmented 10-fold when cultured in medium supplemented with serum-free medium conditioned with LuM1 cells. Because the secretion of M(r) 60,000 gelatinase (MMP2), as well as total protein, by the same cells was not affected under these conditions, the augmentation appears specific for MMP9. The steady-state level of MMP9 mRNA was elevated in LuM1 cells cultured in the presence of the supernatant. The amount of the factor in the culture medium increased with time in culture, indicating that it was produced by the LuM1 cells. It was found to be heat stable but sensitive to trypsin digestion. Conditioned medium from poorly metastatic NM11 cells did not stimulate the secretion of gelatinases by NM11 cells, suggesting that autocrine stimulation of MMP9 secretion is a characteristic of metastatic cells. This factor could account for the augmented secretion of MMP9 by murine tumor cells with spontaneous metastatic potential to the lung.
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PMID:Autocrine factor enhancing the secretion of M(r) 95,000 gelatinase (matrix metalloproteinase 9) in serum-free medium conditioned with murine metastatic colon carcinoma cells. 801 88

The actions of recombinant human fibroblast collagenase (MMP1), purified polymorphonuclear leucocyte collagenase (MMP8) and their N-terminal catalytic domain fragments against cartilage aggrecan and an aggrecan G1-G2 fragment have been investigated in vitro. After activation with recombinant human stromelysin and typsin, both collagenases were able to degrade human and porcine aggrecans to a similar extent. An N-terminal G1-G2 fragment (150 kDa) was used to identify specific cleavage sites occurring within the proteinase-sensitive interglobular domain between G1 and G2. Two specific sites were found; one at an Asn341-Phe342 bond and another at Asp441-Leu442 (human sequence). This specificity of the collagenases for aggrecan G1-G2 was identical with that of the truncated metalloproteinase matrilysin (MMP7), but different from those of stromelysin (MMP3) and the gelatinases (MMP2 or gelatinase A; MMP9 or gelatinase B) which cleave at the Asn-Phe site, but not the Asp-Leu site. In addition, collagenase catalytic fragments lacking C-terminal hemopexin-like domains were tested and shown to exhibit the same specificities for the G1-G2 fragment as the full-length enzymes. Thus the specificity of the collagenases for cartilage aggrecan was not influenced by the presence or absence of the C-terminal domain. Together with our previous findings, the results show that stromelysin-1, matrilysin, gelatinases A and B and fibroblast and neutrophil collagenases cleave at a common, preferred site in the aggrecan interglobular domain, and additionally that both fibroblast and neutrophil collagenases cleave at a second site in the interglobular domain that is not available to stromelysin or gelatinases.
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PMID:Fibroblast and neutrophil collagenases cleave at two sites in the cartilage aggrecan interglobular domain. 821 28

Recent studies have demonstrated the existence of a soluble fibroblast growth factor (FGF) receptor type 1 (FGFR1) extracellular domain in the circulation and in vascular basement membranes. However, the process of FGFR1 ectodomain release from the plasma membrane is not known. Here we report that the 72-kDa gelatinase A (matrix metalloproteinase type 2, MMP2) can hydrolyze the Val368-Met369 peptide bond of the FGFR1 ectodomain, eight amino acids upstream of the transmembrane domain, thus releasing the entire extracellular domain. Similar results were obtained regardless of whether FGF was first bound to the receptor or not. The action of MMP2 abolished binding of FGF to an immobilized recombinant FGFR1 ectodomain fusion protein and to Chinese hamster ovary cells overexpressing FGFR1 The released recombinant FGFR1 ectodomain was able to bind FGF after MMP2 cleavage, suggesting that the cleaved soluble receptor maintained its FGF binding capacity. The activity of MMP2 could not be reproduced by the 92-kDa gelatinase B (MMP9) and was inhibited by tissue inhibitor of metalloproteinase type 2. These studies demonstrate that FGFR1 may be a specific target for MMP2 on the cell surface, yielding a soluble FGF receptor that may modulate the mitogenic and angiogenic activities of FGF.
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PMID:Matrix metalloproteinase 2 releases active soluble ectodomain of fibroblast growth factor receptor 1. 869 46

There is strong evidence that matrix metalloproteinases (MMPs) play a crucial role during osteogenesis and bone remodelling. Their synthesis by osteoblasts has been demonstrated during osteoid degradation prior to resorption of mineralised matrix by osteoclasts and their activities are regulated by tissue inhibitors of metalloproteinases (TIMPs). For this study we developed and utilised specific polyclonal antibodies to assess the presence of collagenase (MMP13), stromelysin 1 (MMP3), gelatinase A (MMP2), gelatinase B (MMP9) and TIMP-2 in both freshly isolated neonatal mouse calvariae and tissues cultured with and without bone-resorbing agents. Monensin was added towards the end of the culture period in order to promote intracellular accumulation of proteins and facilitate antigen detection. In addition, bone sections were stained for the osteoclast marker, tartrate-resistant acid phosphatase (TRAP). In uncultured tissues the bone surfaces had isolated foci of collagenase staining, and cartilage matrix stained for gelatinase B (MMP9) and TIMP-2. Calvariae cultured for as little as 3 h with monensin revealed intracellular staining for MMPs and TIMP-2 in mesenchymal tissues, as well as in cells lining the bone plates. The addition of cytokines to stimulate bone resorption resulted in pronounced TRAP activity along bone surfaces, indicating active resorption. There was a marked upregulation of enzyme synthesis, with matrix staining for collagenase and gelatinase B observed in regions of eroded bone. Increased staining for TIMP-2 was also observed in association with increased synthesis of MMPs. The new antibodies to murine MMPs should prove valuable in future studies of matrix degradation.
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PMID:Localisation of matrix metalloproteinases and TIMP-2 in resorbing mouse bone. 1077 52

Muscle cell migration and extracellular matrix remodeling are essential aspects of muscle development and regeneration. In this study, using a new technique to assess in vivo myoblast migration, we have confirmed previous results showing that the C(2)C(12) myoblast cell line exhibits a higher migratory capacity than primary myoblasts. To test the hypothesis that matrix metalloproteinases (MMPs) are required for the migration of C(2)C(12) myoblasts, we determined whether a synthetic metalloproteinase inhibitor, BB94 (Batimastat), inhibited this process in vivo. Pretreatment with BB94 for 3 days decreased the C(2)C(12) migration at 2 days after cell injection. Since MMP expression is thus necessary for myoblast migration, we have undertaken the identification and characterization of the MMPs expressed by the C(2)C(12) cell line. An RT-PCR assay was used to determine the pattern of MMP mRNA expression by the C(2)C(12) cell line. The proteolytic activities of the MMPs secreted in the culture medium were also assessed by gelatin zymography. The results showed that MMP2 (gelatinase A, 72-kDa type IV collagenase) and MT1-MMP transcripts were expressed by this cell line; however, only MMP2 was secreted and was able to be activated in the extracellular environment. This cell line failed to express MMP9 (gelatinase B, 92-kDa type IV collagenase), stromelysine 2, or stromelysine 3. Our observation that the membrane type MMP (MT1-MMP) transcript is also expressed by the C(2)C(12) suggests that the MMP2 proform (pro-MMP2), may be activated by the MT1-MMP. This possibility is supported by our observation that the pretreatment of C(2)C(12) with concanavalin A (which is known to induce the expression of MT1-MMP) resulted in the processing of pro-MMP2 to its mature form, in a dose-dependent manner. Overexpression and activation of MMP2 in normal myoblasts showed significant increased migration of mouse myoblasts in vivo. Our finding that MMP2 and MT1-MMP gene are coexpressed by C(2)C(12) myoblasts could account for the high migratory capacity of C(2)C(12). Together these results supported the importance of MMP2 and its activation by MT1-MMP for myoblast migration.
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PMID:In vivo migration of transplanted myoblasts requires matrix metalloproteinase activity. 1089 79

The inherited osteolyses or 'vanishing bone' syndromes are a group of rare disorders of unknown etiology characterized by destruction and resorption of affected bones. The multicentric osteolyses are notable for interphalangeal joint erosions that mimic severe juvenile rheumatoid arthritis (OMIMs 166300, 259600, 259610 and 277950). We recently described an autosomal recessive form of multicentric osteolysis with carpal and tarsal resorption, crippling arthritic changes, marked osteoporosis, palmar and plantar subcutaneous nodules and distinctive facies in a number of consanguineous Saudi Arabian families. We localized the disease gene to 16q12-21 by using members of these families for a genome-wide search for homozygous-by-descent microsatellite markers. Haplotype analysis narrowed the critical region to a 1.2-cM region that spans the gene encoding MMP-2 (gelatinase A, collagenase type IV; (ref. 3). We detected no MMP2 enzymatic activity in the serum or fibroblasts of affected family members. We identified two family-specific homoallelic MMP2 mutations: R101H and Y244X. The nonsense mutation effects a deletion of the substrate-binding and catalytic sites and the fibronectin type II-like and hemopexin/TIMP2 binding domains. Based on molecular modeling, the missense mutation disrupts hydrogen bond formation within the highly conserved prodomain adjacent to the catalytic zinc ion.
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PMID:Mutation of the matrix metalloproteinase 2 gene (MMP2) causes a multicentric osteolysis and arthritis syndrome. 1143 82

This study examined the effects of a vegetable extract from Lupinus albus (LU105) on MMPs and TIMPs secreted by human gingival fibroblasts in culture. LU105 was extracted from seeds of L. albus and is freely soluble in water. Gelatin zymography showed that control human gingival fibroblasts maintained in culture for 48 h express pro-MMP2 (progelatinase A) in the culture medium while the active form of MMP2 (gelatinase A), the active form of MMP9 (gelatinase B), and pro-MMP9 (progelatinase B) are not detected. Fibroblasts derived from inflamed gingiva expressed in the culture medium increased amounts of pro-MMP2 (progelatinase A) compared with controls and significant amounts of pro-MMP9 (progelatinase B). LU105 diminished the expression by gingival fibroblasts derived from inflamed tissue of both pro-MMP2 and pro-MMP9. Furthermore LU105 did not modify the amount of TIMP2 expressed in culture by controls or by gingival fibroblasts derived from inflamed tissue. TIMP1 and MMP1 significantly decreased when LU105 was added in the culture media of gingival fibroblasts derived from inflamed tissue compared with control fibroblasts. Thus LU105 seems to offer an opportunity to restore a correct balance between MMP2, MMP9, MMP1, and their natural inhibitors, i.e., TIMP1 and TIMP2 in human inflamed gingiva.
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PMID:Effects of a vegetable extract from Lupinus albus (LU105) on the production of matrix metalloproteinases (MMP1, MMP2, MMP9) and tissue inhibitor of metalloproteinases (TIMP1, TIMP2) by human gingival fibroblasts in culture. 1280 22

Matrix metalloproteinases (MMPs) are endopeptidases considered to be important regulators of the microenvironment of cancer. While MMPs are traditionally associated with the extracellular matrix (ECM), here we provide new evidence from an analysis of gene expression profiles from human tumor tissue that MMP-9 (gelatinase B) is associated with elements of the immune system in a way analogous to the association of other MMPs, such as MMP-2 (gelatinase A), with components of the ECM. An analysis of three independent microarray datasets of lung adenocarcinomas from previous studies [Nat. Med. 8, 816-824 (2002); Proc. Natl. Acad. Sci. USA 98, 13790-13795 (2001); Proc. Natl. Acad. Sci. USA, 98, 13784-13789 (2001)] showed that, in each dataset, out of the set of genes with significant correlations in mRNA expression to the expression of MMP9 (P < 0.005), a highly disproportionate number were found to be annotated in the Locuslink database as having a role in the anti-pathogen response. By comparison, out of the set of genes significantly correlated with the expression of MMP2, a highly disproportionate number were known components of the ECM. The same patterns observed in the lung data for both MMP2 and MMP9 were found as well in an additional published dataset of colon and ovarian adenocarcinomas [Am. J. Pathol. 159, 1231-1238 (2001)]. The results of this study suggest a greater functional role for MMP-9 in the immune response to cancer than what may previously have been thought.
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PMID:Expression of matrix metalloproteinase 9 (MMP-9/gelatinase B) in adenocarcinomas strongly correlated with expression of immune response genes. 1295 92

Positive findings of intoxicant (narcotic) and psychotropic drugs (OPL) have been regularly recorded in clinical patients and deceased persons over the last years at the Institute of Forensic Medicine and Toxicology, 1st Medical faculty and General Teaching Hospital, Prague; stimulants and opioids represent the most frequent cause of death. Their misuse results in damage to various organs. In order to follow the development of pathological changes in the process of remodeling extracellular matrix directly in tissues, the methods of immunohistochemical detection of the matrix metalloproteinases in myocardium and lungs as well as fibrinogen in cardiomyocytes were selected for analysis in a group of 18 deceased individuals. In the intoxication with stimulants we usually demonstrated MMP 2 in the myocardium interstitium, MMP 9 being observed in two cases and MMP 1 in one case. The analysis of lungs always demonstrated MMP 1, especially in the lung interstitium and also on the surface of some alveoli, which accepted the appearance reaching up to "hyaline membranes" as well as in cellular elements of macrophage type and and the same was true for MMP2. Fibrinogen was not always demonstrated in cardiomyocytes. The detection of metalloproteinases was less prominent in the case of opioids. The demonstration of MMP explains well the evolution to more advanced pathomorphological changes, which have been found in myocardium and lungs of OPL users and fits to the nosological status of earlier phases of intoxications with these drugs.
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PMID:[Detection of myocardial and lung injury by psychotropic and narcotic agents by immunohistochemical detection of metalloproteinases]. 1523 26


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