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)

When the monocyte infiltrates a tissue, adhesion to the extracellular matrix provides structural anchors, and the cell may be deformed through these attachments. To test the hypothesis that human monocytes/macrophages are mechanically responsive, we studied the effects of small cyclic mechanical deformations on cultured human monocytes/macrophages. When monocytes/macrophages were subjected to 4% strain at 1 Hz for 24 hours, neither matrix metalloproteinase (MMP)-1 nor MMP-3 was induced; however, in the presence of phorbol myristate acetate, strain augmented MMP-1 expression by 5.1 +/- 0.7-fold (P < 0.05) and MMP-3 expression by 1. 6 +/- 0.1-fold (P < 0.05). In contrast, MMP-9 expression was not changed by mechanical strain in the presence or absence of phorbol myristate acetate. Deformation rapidly induced the immediate early response genes c-fos and c-jun. In addition, mechanical deformation induced the transcription factor PU.1, an ets family member that is essential in monocyte differentiation, as well as mRNA for the M-CSF receptor. These studies demonstrate that human monocytes/macrophages respond to mechanical deformation with selective augmentation of MMPs, induction of immediate early genes, and induction of the M-CSF receptor. In addition to enhancing the proteolytic activity of macrophages within repairing tissues, cellular deformation within tissues may play a role in monocyte differentiation.
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PMID:Biomechanical regulation of human monocyte/macrophage molecular function. 1079 91

Deposition of basic calcium phosphate (hydroxyapatite, octacalcium phosphate and tricalcium phosphate) (BCP) and crystalline calcium pyrophosphate dihydrate (CPPD) is associated with a variety of aging-related pathologies, including osteoarthritis, cartilage degeneration and pseudogout. These diseases of calcium deposition serve as some of the best-studied examples of how calcium-regulated changes in gene expression can directly lead to pathogenic consequences. Tissue damage can result when crystals stimulate cells to release matrix-degrading molecules or secrete cytokines that stimulate the release of matrix-degrading molecules. Exposure of cultured cells to crystals induces expression of cellular proto-oncogenes such as c-fos, c-myc and c-jun, by a calcium-dependent mechanism, and this response can be blocked by a potential therapeutic compound, phosphocitrate. Activation of the c-fos and c-jun genes is directly involved in expression of metalloproteinases such as collagenase and stromelysin, suggesting that crystal-mediated activation of these genes is directly involved in pathogenesis. In this review recent advances in the molecular mechanisms responsible for crystal-mediated cell activation are discussed.
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PMID:Calcium and disease: molecular determinants of calcium crystal deposition diseases. 1082 43

To understand how isolation and explantation of glomeruli affect the function of resident cells, the present study investigated the transcriptional profile of explanted normal glomeruli. We found that ex vivo incubation of glomeruli spontaneously expressed monocyte chemoattractant protein-1 (MCP-1) and stromelysin, the genes regulated by activator protein-1 (AP-1). The expression was suppressed by heparin and quercetin, the drugs with anti-AP-1 activities. The gene expression was preceded by 1) induction of AP-1 components c-fos and c-jun and 2) phosphorylation of extracellular signal-regulated kinase (ERK), p38 mitogen-activated protein (MAP) kinase, and c-Jun NH(2)-terminal kinase (JNK), the upstream inducers/activators of AP-1. Suppression of ERK by PD098059 abrogated induction of c-fos and c-jun, and the p38 MAP kinase inhibitor SB203580 attenuated c-fos expression. Furthermore, treatment with either PD098059, SB203580, or the JNK-AP-1 inhibitor curcumin diminished the expression of MCP-1 and stromelysin. The transcriptional profile of glomerular cells thus alters dramatically after explantation of glomeruli. It is, at least in part, due to activation of multiple MAP kinases that lead to induction of AP-1-dependent gene expression.
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PMID:Spontaneous shift in transcriptional profile of explanted glomeruli via activation of the MAP kinase family. 1105 56

In an effort to elucidate the role of mechanical stimuli in rheumatoid arthritis, we determined mRNA levels of matrix metalloproteinase (MMP)-1, MMP-3, MMP-13, tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2, and three transcription factors (c-fos, ets-1, and ets-2) under two mechanical shearing conditions as well as simulated unloading. Human synovial cell cultures (MH7A and RA99-01), derived from rheumatoid arthritis patients, were grown for 1 h under mechanical stimuli and the transcript level was assayed by the reverse transcription-polymerase-chain reaction procedure. First, gentle shearing, estimated at approximately 1 dyn/cm(2), induced a consistent decrease in mRNA level of MMP-1, MMP-3, MMP-13, and ets-1 and an increase in the transcript level of TIMP-1, TIMP-2, c-fos, and ets-2. Second, intermediate shearing, estimated at approximately 6 dyn/cm(2), elevated the mRNA level of all MMPs, TIMPs, and the three transcription factors. Third, minimum mRNA level of c-fos, ets-1, and ets-2 was achieved under control conditions at rest, gentle shearing, and simulated unloading, respectively. These in vitro results support a stimulus-dependent transcriptional regulation of MMPs, TIMPs, and transcription factors in cell cultures, suggesting a potential role of shear stress in tissue degradation and prevention in rheumatic joints.
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PMID:Messenger-RNA expression of matrix metalloproteinases, tissue inhibitors of metalloproteinases, and transcription factors in rheumatic synovial cells under mechanical stimuli. 1124 61

Proteasome inhibitors, the well-known inhibitors of NF-kappaB, are recently considered therapeutic agents for inflammation. However, the anti-inflammatory properties of these agents have not been fully evaluated. In this report we describe a novel effect of proteasome inhibitors on the expression of monocyte chemoattractant protein 1 (MCP-1) in mesangial cells. We found that proteasome inhibitor MG132 dose-dependently induced expression of MCP-1 at the transcriptional level. The stimulatory effect was similarly observed with other proteasome inhibitors (proteasome inhibitor 1 and lactacystin) and in other cell types (NRK fibroblasts). The 5'-flanking region of the MCP-1 gene contains multiple AP-1 sites. To explore the mechanisms involved, we examined the effects of proteasome inhibition on the AP-1 pathway. Northern blot analysis showed that MG132 rapidly induced the expression of c-jun, but not c-fos. Immunoblot analysis showed that MG132 prevented degradation of c-Jun protein. Kinase assay revealed that c-Jun N-terminal kinase (JNK) was rapidly activated by MG132. Consistent with these results, a reporter assay showed that AP-1 activity was up-regulated after treatment with MG132. Curcumin, a pharmacological inhibitor of the JNK-AP-1 pathway, abrogated the induction of MCP-1 by MG132. Similarly, stable transfection with a dominant-negative mutant of c-Jun attenuated both MG132-induced activation of AP-1 and expression of MCP-1. The transcriptional activation by proteasome inhibitors was observed not only in MCP-1, but also in other AP-1-dependent genes, including stromelysin and mitogen-activated protein kinase phosphatase 1. These data revealed that proteasome inhibition triggered the expression of MCP-1 and other genes via the multistep induction of the JNK-c-Jun/AP-1 pathway.
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PMID:Unexpected transcriptional induction of monocyte chemoattractant protein 1 by proteasome inhibition: involvement of the c-Jun N-terminal kinase-activator protein 1 pathway. 1146 28

Here, we have examined the role of distinct MAPK pathways in the regulation of collagenase-1 (matrix metalloproteinase (MMP)-1) and stromelysin-1 (MMP-3) expression by human skin fibroblasts. Tumor necrosis factor-alpha rapidly and transiently activated ERK1/2 and JNK in fibroblasts, whereas the activation of p38 MAPK was more persistent. Inhibition of p38 activity by SB203580 markedly (by 80-90%) inhibited induction of MMP-1 and MMP-3 expression by tumor necrosis factor-alpha, whereas blocking the activation of ERK1/2 by PD98059 had no effect. Activation of endogenous ERK1/2 by adenovirus-mediated transfer of constitutively active MEK1 resulted in potent induction of MMP-1 and MMP-3 expression. Activation of endogenous or adenovirally expressed p38 alpha by adenovirally delivered constitutively active MKK3b and MKK6b also enhanced MMP-1 and MMP-3 expression and augmented the up-regulatory effect of ERK1/2 activation on the expression of these MMPs. Activation of ERK1/2 resulted in induction of c-jun, junB, and c-fos expression, whereas activation of p38 alone had no effect. In contrast, activation of p38 alpha resulted in marked stabilization of MMP-1 and MMP-3 mRNAs. These results identify two distinct and complementary signaling mechanisms mediating induction of MMP-1 and MMP-3 expression in dermal fibroblasts: AP-1-dependent transcriptional activation via the ERK1/2 pathway and AP-1-independent enhancement via p38 alpha MAPK by mRNA stabilization. It is conceivable that both modes of action play an important role in controlling the proteolytic phenotype of fibroblasts, e.g. in wound repair and tumor invasion.
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PMID:Activation of p38 alpha MAPK enhances collagenase-1 (matrix metalloproteinase (MMP)-1) and stromelysin-1 (MMP-3) expression by mRNA stabilization. 1206 Jun 61

We previously reported that follistatin-related protein (FRP)/TSC-36 was one of the target antigens of autoantibodies in rheumatoid arthritis (RA) and that the appearance of serum autoantibodies to FRP correlated to disease activity in RA. However, the significance of FRP in autoimmunity remained to be explained due to the unknown function of FRP. Here, we disclose in part the function of FRP. Transforming growth factor (TGF)-beta augmented FRP gene expression in synovial cells. FRP reduced synovial production of matrix metalloproteinase (MMP)-1, MMP-3 and prostaglandin E(2), potent agonists of joint destruction in RA. In contrast, autoantibodies to FRP from patients with RA increased their production by blocking FRP activity, probably in the autocrine system. Moreover, FRP down-regulated synovial expression of FOS (c-fos), which seemed responsible for the reduction in MMP-1 and MMP-3 caused by FRP. Therefore, FRP and its autoantibody can be regarded as defensive and offensive factors respectively in rheumatoid arthropathy. The major epitope of autoantibodies to FRP was mapped to the sequence LKFVEQNE (residues 169-176) and homologous sequences were found in proteins from Escherichia coli, Epstein-Barr virus, etc. FRP and its autoantibody may provide some clues to elucidate the process of disease development and a new approach to the design of therapeutics in RA.
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PMID:Potential preventive effects of follistatin-related protein/TSC-36 on joint destruction and antagonistic modulation of its autoantibodies in rheumatoid arthritis. 1250 27

To improve the therapeutic benefit of hyperthermia, we examined changes of global gene expression after heat shock using DNA microarrays consisting of 12 814 clones. HeLa cells were treated for 1 h at 44 degrees C and RNA was extracted from the cells 0, 3, 6, and 12 h after heat shock. The 664 genes that were up or down-regulated after heat shock were classified into 7 clusters using fuzzy adaptive resonance theory (fuzzy ART). There were 41 genes in two clusters that were induced in the early phase after heat shock. In addition to shock response genes, such as hsp70 and hsp40, the stress response genes c-jun, c-fos and egr-1 were expressed in the early phase after heat shock. We also found that expression of matrix metalloproteinase 3 (MMP-3) was enhanced during the early response. We therefore investigated the role of MMP-3 in the heat shock response by examining HeLa cell survival after heat treatment in the presence and absence of an MMP-3 inhibitor, N-isobutyl-N-(4-methoxyphenylsulfonyl)glycylhydroxamic acid (NNGH) or N-hydroxy-2(R)-[[4- methoxysulfonyl](3-picolyl)amino]-3-methylbutaneamide hydrochloride (MMI270). The number of surviving cells 3 days after heat treatment significantly decreased, reaching 3.5% for NNGH and 0.2% for MMI270. These results indicate that the MMP-3 inhibitors enhanced heat shock-induced cell death and behaved as stress enhancers in cancer cells. This valuable conclusion was reached as a direct result of the gene expression profiling that was performed in these studies.
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PMID:Screening of stress enhancer based on analysis of gene expression profiles: enhancement of hyperthermia-induced tumor necrosis by an MMP-3 inhibitor. 1284 76

The significance of activating proteins (AP-1), c-fos, c-jun and jun B relative to the AP-1 responsive metallothionein, collagenase and stromelysin gene expression in the pathophysiology of osteoarthritis (OA) was investigated. The 'early' c-fos, c-jun and jun-B mRNAs were ubiquitously expressed in normal and OA human knee synovial membranes. There was no strict correlation between expression of these and the AP-1 responsive, collagenase and stromelysin gene expression. Interestingly, the total metallothionein (MT) and the AP-1 responsive, MT-IIA gene-specific mRNAs were greatly diminished in OA compared with normal synovial membranes. The possible role of reduced expression of MT and trace metals in OA pathophysiology is discussed. Collectively, these data demonstrate a discoordinate expression of AP-1 encoding and their target genes in synovium.
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PMID:Distinct expression pattern of early- and late-response genes in normal and osteoarthritic human synovial membranes. 1544 20

Matrix metalloproteinases (MMPs) play a key role in cellular invasion and growth. Recent observations on tumor tissue samples suggest that MMP activity is altered in relation to cell density. Therefore, we examined MMP(-1,-2,-3,-8,-9,-10,-11 and -13) and TIMP-1/-2 expression of well-defined cell densities in breast carcinoma cell lines with differing in vivo tumorigenicity/invasiveness (MCF-7 < MDA-MB-468 < MDA-MB-231 < MDA-MB-435). Chemoinvasion assays were performed to link the in vitro data to the in vivo behavior. In accord with previous in vivo data, expression levels of most MMPs decreased significantly with increasing cell density and correlated well with a lower in vitro invasiveness of confluent cells. Since these data suggested that cell density regulates transcription and the promoter regions of most MMPs have AP-1 transcription factor binding consensus sequences, we tested whether functional AP-1 protein was involved in the mechanism of MMP downregulation by cell density. A role for AP-1 was confirmed by over-expression of c-Jun and c-fos in confluent MDA-MB-231 cells, showing with c-Jun increased MMP-2 (5-fold), MMP-3 (1.6-fold), and MMP-9 (160-fold) expression, as well as enhanced invasive potential, while TIMP-1 expression was down-regulated (2-fold) when compared to vector controls. Our data provide clear evidence that cell density regulates major MMPs and TIMPs which are controlled by AP-1 activity so that ultimately a major regulation pathway for the control of the invasive potential of tumor cells is presented.
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PMID:Cell density-dependent regulation of matrix metalloproteinase and TIMP expression in differently tumorigenic breast cancer cell lines. 1577 90


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