Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.17 (MMP-3)
 3,419 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The attachment of the blastocyst to the uterine luminal epithelium and the subsequent invasion by trophoblast cells through the stroma and deciduum occur in a highly regulated manner by remodeling of the extracellular matrix. We investigated the temporal and spatial expression of mRNAs for four matrix metalloproteinases (MMPs; MMP-2 [gelatinase A], MMP-3 [stromelysin 1], MMPs; MMP-2 [gelatinase B], and MMP-13 [collagenase 3]) and tissue inhibitors of metalloproteinases (TIMPs; TIMP-1, TIMP-2, and TIMP-3) in the mouse uterus from days 1 to 8 of pregnancy. Northern blot analyses showed the transcripts for MMP-2, MMP-3, RNA on these days. However, MMP-13 mRNA was not detected in the uterus, and only weak signals for MMP-3 mRNA were detected in the myometrium. Striking expression was observed with MMP-2 mRNA in the subepithelial stroma on days 3-5. With the progression of decidualization on day 6, signals were primarily in the secondary decidual zone. On day 8, MMP-2 mRNA was localized at the site of placenta formation in the mesometrial pole. Signals for MMP-9 mRNA were first detected in a small population of stromal cells exclusively at the site of implantation on day 5 at the antimesometrial pole. However, the most pronounced expressed was noted in trophoblast giant cells on day 8. TIMP-1 mRNA was present in the myometrium on day 1. On days 2-5, modest signals were detected in the stroma, and on days 6 and 8, they were in the secondary decidual zone. Localization of TIMP-2 mRNA was similar to that of TIMP-1 except it was restricted to the stroma on day 1. The regulation of TIMP-3 was more pronounced. While a gradual increase in signals was observed in stromal cells from days 1 to 4, strong signals were detected in antimesometrial stromal cells at the sites of blastocyst attachment on day 5. On days 6 and 7, even stronger signals were present in the primary decidual zone surrounding the embryo, and on day 8 signals were localized primarily in the mesometrial decidual bed. These results suggest that MMP-2 may participate in the early phase of decidualization and neovascularization required for placentation. The restricted MMP-9 expression in stromal cells on day 5 and in trophoblast giant cells on day 8, coupled with the expression of TIMP-3 in the stroma surrounding the embryo, suggests that a fine balance between MMP-9 and TIMP-3 may regulate trophoblast invasion in the uterus.
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PMID:Expression of matrix metalloproteinases and tissue inhibitors of metalloproteinases in the mouse uterus during the peri-implantation period. 929 79

To evaluate the role of matrix metalloproteinases (MMPs) and their specific tissue inhibitors (TIMPs) in the pathogenesis of the structural damage and cystic lesions found in pulmonary lymphangioleiomyomatosis (LAM), immunohistochemical studies were made of the localization of MMP-1, MMP-2, MMP-3, MMP-9, TIMP-1, TIMP-2, HMB-45, and type IV collagen in sections of lung biopsy specimens from four patients with this disorder. These studies showed increased immunoreactivity compared with that in normal bronchiolar and vascular smooth muscle cells, of MMP-2 and, to a lesser extent, MMP-9 and MMP-1 in the LAM cells. MMP-2 was also localized in some elastic fibers and in the basement membranes of LAM cells and overlying epithelial cells. The basement membranes in both of these sites often showed colocalization of MMP-2 and type IV collagen. Some epithelial basement membranes showing this colocalization were disrupted. These changes were not accompanied by increased immunoreactivity for TIMPs. Taken together with previous observations showing structural damage to elastic fibers and collagen fibrils, and with the absence of demonstrable neutrophil or pancreatic types of elastase, these findings suggest that MMP-2 and MMP-9 (both of which can degrade elastin as well as collagens) are responsible for the connective tissue destruction and cyst formation in LAM.
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PMID:Immunohistochemical study of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) in pulmonary lymphangioleiomyomatosis (LAM). 930 32

The temporal relationship of matrix metalloproteinases (MMPs) and a specific tissue inhibitor (TIMP-1) has been examined by reverse transcription-polymerase chain reaction and substrate zymography, after balloon catheter angioplasty of the rat carotid artery. The contralateral uninjured carotid artery was used as a comparative control. Of the MMPs examined, only MMP-2 (72-kDa gelatinase) was produced constitutively by normal uninjured arteries. After injury, MMP-2 mRNA levels fell compared with the uninjured arteries; by 24 hours, levels had increased 2-fold. Zymography showed that the inactive form of MMP-2 predominated in uninjured vessels, but after injury, the level of the active form was increased. MMP-9 (92-kDa gelatinase) mRNA levels and activity peaked at 6 hours after injury and were still detectable at 7 days. MMP-3 (stromelysin) expression was detectable at low levels as early as 2 hours after injury and showed an approximate 2-fold increase of expression at 7 days. The presence of the active protein paralleled the mRNA expression. The inhibitor TIMP-1 mRNA was first detected 6 hours after injury and showed a marked peak of expression at 24 hours; however, no expression was detected by 7 days. The presence of a constitutively expressed, low molecular weight caseinolytic enzyme (27 kDa) was observed, and the induction of a caseinolytic enzyme (30 kDa) was noted that was induced as early as 2 hours after injury, peaked at 6 hours, and was barely detectable by 7 days. These results demonstrate that the process of extracellular matrix breakdown by MMPs after balloon catheter-induced injury is controlled by a tightly regulated temporal response by the genes responsible for the production of these enzymes and their inhibitor and by post-translational activation of the proenzymes.
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PMID:Expression of matrix metalloproteinases and their inhibitor TIMP-1 in the rat carotid artery after balloon injury. 932 85

beta 2-Microglobulin (beta 2-m) is a major constituent of amyloid fibrils in hemodialysis-associated amyloidosis (HAA), a serious complication in patients on long-term hemodialysis. The most distinctive pathological feature of HAA is the deposition of amyloid fibrils with subsequent articular inflammation and destruction. However, the pathological role of beta 2-m is not well known at present. We investigated the effects of beta 2-m on the production of proteinases from synovial fibroblasts isolated from patients with rheumatoid arthritis. beta 2-m stimulated synovial fibroblasts to produce stromelysin, a neutral matrix metalloproteinase (MMP-3). The production of MMP-2 and of a tissue inhibitor of metalloproteinase-1 (TIMP-1) were not enhanced by beta 2-m-treated synovial fibroblasts. Stromelysin is capable of degrading several components of the extracellular matrix and believed to be the key enzyme causing articular destruction in inflammatory joint diseases. Our results suggest a novel role for beta 2-m in articular inflammation and destruction mediated by stromelysin in HAA.
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PMID:Beta 2-microglobulin induces stromelysin production by human synovial fibroblasts. 934 81

Matrix metalloproteinases (MMPs) are responsible for the degradation of extracellular matrix components and are secreted by a variety of cells including human endothelial cells. Because alpha-thrombin is known to interact with matrix components and has been shown to activate latent MMP-2 in human umbilical vein endothelial cells, we investigated whether human alpha-thrombin could also regulate other MMPs secreted by the human saphenous vein or mammary artery endothelial cells (EC). After treatment of EC with increasing concentrations of thrombin for different periods of time, a significantly higher gelatinolytic activity of both MMP-1 and MMP-3 was observed in addition to MMP-2 activation. The effect of thrombin was time and dose-dependent, reaching a maximum at 24 hours. After treatment with 5 NIH U/ml thrombin for 24 hours, Western blotting revealed 9.5- and 4.4-fold increases over control values for MMP-3 and MMP-1, respectively. The synthetic thrombin receptor agonist peptide SFLLRNPNDKYEPF fully reproduced the action of thrombin, whereas chemical inactivation of the catalytic site of thrombin abolished its effect on MMP-1 and MMP-3. Thrombin and SFLLRNPNDKYEPF both induced MMP-3 mRNA synthesis but had no significant influence on constitutive MMP-1 mRNA levels. These results demonstrate that thrombin not only activates latent MMP-2 but also modulates MMP-1 and MMP-3 production in EC, this latter effect being mediated by the G-protein-coupled thrombin receptor. Hence, our present data provide evidence to support the suspected role of thrombin in tissue remodeling and angiogenesis.
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PMID:Thrombin receptor-mediated increase of two matrix metalloproteinases, MMP-1 and MMP-3, in human endothelial cells. 935 56

Cultured fibroblasts from patients with systemic sclerosis (SSc) and normal individuals were examined for gene expression of types I and III collagen, decorin, matrix metalloproteinases (MMP) MMP-1, MMP-2, and MMP-3, tissue inhibitors of metalloproteinases (TIMP) TIMP-1 and TIMP-2, urokinase- and tissue-type plasminogen activators (u-PA and t-PA). Fibroblasts from patients with early stage SSC (less than 1 year duration of disease) exhibited higher levels of types I and III procollagen, decorin, MMP-1, MMP-3, TIMP-1, and PAs than those from normal individuals. The gene expression of procollagen alpha 1(I) and TIMP-1 mRNAs were increased, but those of decorin, MMP-1, MMP-2, and MMP-3 were decreased, in fibroblasts from SSc patients with mid-stage SSc (2 to 4 years duration) as compared with those from normal individuals. In contrast, no significant difference in gene expression was found between fibroblasts from normal individuals and from patients with late-stage SSc (more than 6 years duration). These results suggest that gene expression of collagen, decorin, and degrading factors is dynamically modulated during fibrillogenesis. The responses of procollagen alpha 1(I) mRNA to IL-1 and TGF-beta were lower in fibroblasts from SSc patients with early and mid-stage disease, but not in those from patients with-late stage disease, than in control fibroblasts, which indicates that these cytokines may be involved in the earlier phases of fibrosis in SSc.
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PMID:Gene expression of types I and III collagen, decorin, matrix metalloproteinases and tissue inhibitors of metalloproteinases in skin fibroblasts from patients with systemic sclerosis. 937 15

Phospholipase C (PLC) is a putative virulence factor of several pathogenic bacteria. We studied if exogenous PLC would perturb epithelial behavior in infected tissues. Gelatin and casein zymography of cell culture medium indicated that the broad-spectrum PLC of Bacillus cereus induced matrix metalloproteinase (MMP) production in epithelial cells of human skin (NHEK), human gingiva (HGE), and porcine periodontal ligament (PLE). In all three cell types, the strongest increase (ninefold) at 0.1 U/ml was seen in the MMP-9 (92-kDa gelatinase) activity, and the effect was dose dependent in the range of 0.1 to 1.0 U/ml. A relatively weaker increase (twofold) in MMP-2 (72-kDa gelatinase) was also observed in each cell type. PLC induction of MMP-3 (48-kDa stromelysin) was also seen in NHEK and HGE on gelatin and more sensitively for PLE by casein zymography (fivefold). Total gelatinolytic activity as measured by degradation of 14C-labeled denatured type I collagen increased by about 18-fold (NHEK), 12-fold (HGE), and 14-fold (PLE). Northern analysis showed a clear increase in the MMP-9, and a minor increase in MMP-3 mRNA levels but no significant increase in MMP-2 mRNA levels. Further studies with PLE revealed that MMP-9 induction by PLC progressively increased with the length of cell culture time in the absence of serum. PLC induction of MMPs was polar, with MMP-9 and MMP-3 secreted primarily in the apical direction and MMP-2 secreted mainly in the basal direction. The PLC effect was blocked by neomycin, an inhibitor of the phosphoinositol signal pathway. No significant effects were observed in MMP expression with the calcium ionophore A23187 or phospholipase A2. Morphologically, PLC treatment resulted in reduced contacts between the cultured cells and loss of the cell surface microvilli. These results suggest that PLC secreted by bacterial pathogens may disrupt epithelium of infected tissue and increase the subepithelial tissue destruction through induction of MMPs.
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PMID:Bacterial phospholipase C upregulates matrix metalloproteinase expression by cultured epithelial cells. 939 78

Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is synthesized as a membrane-anchored precursor that is cleaved to release the soluble mature growth factor. The two forms are active as juxtacrine and paracrine/autocrine growth factors, respectively. The enzymes that process the HB-EGF transmembrane form are unknown. Accordingly, an in vitro assay was established using a fusion protein in which alkaline phosphatase (AP) replaced the transmembrane and cytoplasmic domains of HB-EGF (HB-EGF JM-AP). The fusion protein was anchored to agarose beads coated with anti-AP antibodies. Several matrix metalloproteinases (MMPs) were tested for the ability to release soluble HB-EGF in the in vitro system. MMP-3 released soluble 12-kDa immunoreactive and mitogenic HB-EGF within 30 min. On the other hand neither MMP-2 nor MMP-9 had any cleavage activities. A non-cleavable mutant was prepared by replacing the juxtamembrane (JM) region of HB-EGF with the JM region of CD4. The mutant HB-EGF, which in its full-length form was as active a juxtacrine growth factor as was the wild type HB-EGF in vivo, was not cleaved by MMP-3 in the in vitro assay. The C-terminal portion of the cleaved HB-EGF JM-AP that remained attached to the anti-AP beads was N-terminally sequenced and the MMP-3 cleavage site was determined to be Glu151-Asn152, a site within the JM domain. MMP-3 treatment also released soluble HB-EGF in vivo from MC2 cells expressing transmembrane HB-EGF precursor, at a level of about 2-fold above control. It was concluded that MMP-3 cleaves HB-EGF at a specific site in the JM domain and that this enzyme might regulate the conversion of HB-EGF from being a juxtacrine to a paracrine/autocrine growth factor.
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PMID:Matrix metalloproteinase-3 releases active heparin-binding EGF-like growth factor by cleavage at a specific juxtamembrane site. 939 17

Al-trans retinoic acid (RA) enhanced human, S-type, SK-N-SH neuroblastoma cell invasion of reconstituted basement membrane in vitro but did not induce terminal differentiation of this cell line. In contrast to basal invasion, which was urokinase (uPA)- and plasmin-dependent, RA-enhanced invasion was dependent on tissue-type plasminogen activator (t-PA) and plasmin activity. Neither basal nor RA-enhanced invasion involved TIMP-2 inhibitable metalloproteinases. Enhanced invasion was associated with the induction of t-PA expression, increased expression of the putative t-PA receptor amphoterin, increased association of t-PA with cell membranes and increased net membrane-associated PA activity. Enhanced invasion was not associated with significant changes in the expression of uPA or its membrane receptor UPAR; plasminogen activator inhibitors PAI-1 and PAI-2; metalloproteinases MMP-1, MMP-2, MMP-3, MMP-9 and membrane type MMP1; or tissue inhibitors of metalloproteinases TIMP-1 and TIMP-2. RA stimulated the association of t-PA with the external cell membrane surface, which could be inhibited by heparin sulphate but not by mannose sugars or chelators of divalent cations, consistent with a role for amphoterin. Our data indicate that RA can promote the malignant behavior of S-type neuroblastoma cells refractory to RA-mediated terminal differentiation by enhancing their basement membrane invasive capacity. We suggest that this results from the action of a novel, RA-regulated mechanism involving stimulation of t-PA expression and its association with the cell membrane leading to increased PA-dependent matrix degradation.
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PMID:Retinoic acid-enhanced invasion through reconstituted basement membrane by human SK-N-SH neuroblastoma cells involves membrane-associated tissue-type plasminogen activator. 939 56

Tissue remodelling involving extracellular matrix (ECM) turnover plays a major role in leiomyoma growth and regression, regulated by the combined action of matrix metalloproteinases (MMPs) and the tissue inhibitors of MMPs (TIMPs). We postulated that leiomyomata express MMP and TIMP mRNA and protein, and their expression is inversely regulated during tumour growth and gonadotrophin releasing hormone agonist (GnRHa)-induced regression. We therefore examined the expression of mRNA and protein for MMPs (interstitial collagenase, MMP-1; gelatinases, MMP-2 and MMP-9; and stromelysin, MMP-3) and TIMPs (TIMP-1 and TIMP-2) in leiomyoma and matched unaffected myometrium from GnRHa (lupron)-treated and untreated patients. Reverse transcription-polymerase chain reaction (RT-PCR) and restriction enzyme analysis revealed that leiomyomata and myometrium expressed MMP-1, -2, -3 and -9, as well as TIMP-1 and -2 mRNA. Quantitative RT-PCR indicated that leiomyomata and myometrium during the secretory phase of the menstrual cycle expressed higher levels of MMP and TIMP mRNA compared to the proliferative phase (P < 0.05), with low to undetectable levels of MMP-1, -2 and -3 mRNA in the tumours. GnRHa therapy induced an overall reduction in MMP and TIMP mRNA expression in both leiomyomata and myometrium, but a significant decrease in TIMP-1, and an increase in MMP mRNA expression compared with untreated tumours (P < 0.05). Immunohistochemically, MMP-1, -2, -3 and -9 and TIMP-1 and -2 proteins were localized in leiomyomata and myometrial smooth muscle cells, arteriole wall and connective tissue fibroblasts, with an overall increase in MMP and a decrease in TIMP staining intensity in GnRHa-treated groups. The results suggest that MMP and TIMP expression in leiomyoma and myometrium are hormonally regulated, and that GnRHa-induced tumour regression is accompanied by an increase in MMP expression with a concomitant decrease in TIMP-1 expression, which may potentially provide an environment favouring ECM degradation.
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PMID:Differential expression of matrix metalloproteinases and their tissue inhibitors in leiomyomata: a mechanism for gonadotrophin releasing hormone agonist-induced tumour regression. 943 28


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