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)

A commercial preparation of 800-kDa hyaluronic acid (HA), (ARTZ from Seikagaku, Inc.), has been used as a therapeutic intervention in the treatment of osteoarthritis (OA). We tested the effect of this HA form, HA/800, in an in vitro cartilage chondrolytic system in which a specific amino-terminal 29-kDa fragment of fibronectin (Fn-f) penetrates cartilage tissue to activate chondrocytes to amplify two major chondrolytic activities: suppression of proteoglycan (PG) synthesis and induction of matrix metalloproteinases. We report that HA/800 did not block damage by Fn-f in serum free cartilage cultures. However, HA/800 was effective in blocking the ability of 100 nM Fn-f to cause the degradation and release of half of the total cartilage PG from cartilage in 10% serum/DMEM cultures. While the Fn-f caused a half-time for PG release of 3 days, continuous exposure to 0.1 or 1 mg/ml HA/800 slowed the half-time to 12 days. Further, a single 1 day pre-incubation with 0.1 or 1 mg/ml HA/800 was sufficient to decrease the half-time of 100 nM Fn-f mediated PG depletion to 7 and 12 days, respectively. HA/800 completely blocked the effect of 10 nM Fn-f. Blocking of Fn-f-mediated cartilage PG depletion was associated with a decreased concentration of Fn-f on the superficial cartilage surface and decreased penetration into the cultured cartilage tissue. Further, the two major chondrolytic activities of the Fn-f, suppression of synthesis of PG and enhanced release of stromelysin-1, were suppressed by HA/800. HA/800 also partially restored PG in cartilage first damaged with the Fn-F. We conclude that HA/800 slows Fn-f-mediated cartilage chondrolysis in vitro and has some reparative potential. The damage blocking activity appears to be associated with the ability of HA/800 to block penetration of the Fn-f, rather than with direct effects on cartilage tissue.
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PMID:Hyaluronic acid suppresses fibronectin fragment mediated cartilage chondrolysis: I. In vitro. 949 38

Tumor cell invasion relies on cell migration and extracellular matrix proteolysis. We investigated the contribution of different integrins to the invasive activity of mouse mammary carcinoma cells. Antibodies against integrin subunits alpha6 and beta1, but not against alpha1 and alpha2, inhibited cell locomotion on a reconstituted basement membrane in two-dimensional cell migration assays, whereas antibodies against beta1, but not against alpha6 or alpha2, interfered with cell adhesion to basement membrane constituents. Blocking antibodies against alpha1 integrins impaired only cell adhesion to type IV collagen. Antibodies against alpha1, alpha2, alpha6, and beta1, but not alpha5, integrin subunits reduced invasion of a reconstituted basement membrane. Integrins alpha1 and alpha2, which contributed only marginally to motility and adhesion, regulated proteinase production. Antibodies against alpha1 and alpha2, but not alpha6 and beta1, integrin subunits inhibited both transcription and protein expression of the matrix metalloproteinase stromelysin-1. Inhibition of tumor cell invasion by antibodies against alpha1 and alpha2 was reversed by addition of recombinant stromelysin-1. In contrast, stromelysin-1 could not rescue invasion inhibited by anti-alpha6 antibodies. Our data indicate that alpha1 and alpha2 integrins confer invasive behavior by regulating stromelysin-1 expression, whereas alpha6 integrins regulate cell motility. These results provide new insights into the specific functions of integrins during tumor cell invasion.
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PMID:alpha1 and alpha2 integrins mediate invasive activity of mouse mammary carcinoma cells through regulation of stromelysin-1 expression. 995 Jun 76

Synovial fluid basic calcium phosphate (BCP) crystals are markers of severe joint degeneration in osteoarthritis. These crystals are mitogenic and induce protooncogene expression and matrix metalloproteinase (MMP) synthesis and secretion in human fibroblasts, effects that are specifically blocked by phosphocitrate (PC). We have recently determined that crystals transduce signals to the nucleus via the activation of the p42 and p44 mitogen-activated protein (MAP) kinases (Nair et al., 1997, J Biol Chem 272:18920-18925). Treatment of human fibroblasts (HF) with BCP induces phosphorylation of p42/44 MAPK, which is inhibited by PC in a dose-dependent manner. Blocking of p42/44 MAPK signal transduction with an inhibitor (PD98059) of MEK1, an upstream activator of MAPKs, reduces crystal-induced p42/44 MAPK activation and significantly inhibits crystal-induced cell proliferation. Based on these findings, we sought to determine the role of the p42/44 MAPK signal transduction pathway in crystal-induced expression of matrix MMPs. We demonstrate suppression of crystal-induced MMPs via the utilization of two different MEK inhibitors: PD98059 and the recently described U0126, a novel inhibitor of MEK1 and MEK2. Treatment of HF with PD98059 blocks the induction of crystal-stimulated collagenase 1 (MMP-1) and stromelysin (MMP-3) expression. PD98059 and PC reduced the level of crystal-induced MMP-1 and MMP-3 mRNA expression to that observed in nonstimulated cells. Likewise, PD98059 treatment of HF blocked the epidermal growth factor (EGF)- and crystal-induced increases in MMP-1 and MMP-3 protein expression and secretion as demonstrated by Western blotting and zymography. Treatment of HF with U0126 inhibits EGF-induced phosphorylation of p42/44 MAPK as well as crystal- and EGF-induced upregulation of MMP-1 mRNA. Additionally, we demonstrate that treatment of HF with BCP, EGF, or PD98059 does not significantly alter levels of gelatinase A (MMP-2) mRNA and protein expression.
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PMID:Basic calcium phosphate crystal induction of collagenase 1 and stromelysin expression is dependent on a p42/44 mitogen-activated protein kinase signal transduction pathway. 1039 91

In the present study we investigated whether the collagen types I, III and V affect the activity of fibroblasts obtained from rabbit periosteum. The cells were cultured on plates either or not coated with different amounts of collagen type I, III or V and analyzed for their attachment, DNA synthesis and the expression and activity of matrix metalloproteinases (MMPs). Our data show that the three collagen types promoted attachment and spreading of the cells and stimulated DNA synthesis when used in relatively low concentrations. High concentrations of type V-but not of type I or III-proved to inhibit thymidine incorporation. The expression and activity of matrix metalloproteinase 1 (MMP-1; interstitial collagenase) decreased under the influence of relatively low amounts of collagen (<40 microg/well), whereas higher levels increased its release. Matrix metalloproteinase 2 (MMP-2; gelatinase A) was up-regulated by the different types of collagen; the active fraction of stromelysin-1 (MMP-3) decreased. Accordingly, the mRNA expression of MMP-1 and -3 were reduced. The expression of MMP-2 mRNA, however, proved to be unaffected. Blocking antibodies to beta(1)-integrin or echistatin increased the level of MMP-1 but had no effect on MMP-2. All parameters tested were similarly affected by type I and III collagen, whereas the effect of type V was always less. We conclude that the collagen types I, III and V provide different sets of signals for fibroblasts that differently modulate their proliferation and MMP expression.
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PMID:Collagen type I, III and V differently modulate synthesis and activation of matrix metalloproteinases by cultured rabbit periosteal fibroblasts. 1285 32

Squamous cell carcinoma (SCC) of the oral cavity is a highly invasive tumour of stratified squamous epithelium that spreads through degradation of the basement membrane (BM) and extracellular matrix (ECM). There are currently no reliable tissue or serum markers to predict whether the tumour has metastasized at the time of diagnosis. Verrucous carcinoma (VC) of the oral cavity is a rare low-grade variant of oral SCC that penetrates into the subepithelial connective tissue. Many matrix metalloproteinases (MMPs), such as MMP-1, -2, -7, -9, -13, and -14, as well as integrin receptors have been implicated in cancer invasion. Integrin alphavbeta6 is induced in SCC and appears to be involved in up-regulation of MMP-9 expression by oral keratinocytes and promotion of their migration. The aim of this study was to investigate whether the pattern of MMP expression or that of alphavbeta6 integrin contributes to the differences in the biological behaviour of oral SCC and VC. The results show that the less aggressive nature of oral VC may be connected to its MMP expression profile. Typically, VCs were devoid of epithelial MMP-3, -7, -9, -12 and -13 expression, compared with SCCs. MMP-19 was expressed by epithelial keratinocytes in hyperproliferative areas of verrucous hyperplasia, VC, and SCC, but was absent in the invasive cancer cell nests of SCC. MMP-26 was expressed by hyperproliferative keratinocytes in VC as well as by invasive cancer cells in SCCs. MMP-10 was expressed widely in the epithelium of all SCC specimens. alphavbeta6 integrin expression was also detected in some cases of epithelial hyperplasia but was significantly more abundant in cancers at the invasive front. The absence of MMP-7, -9 and -12 from epithelial cells may serve as a good prognostic marker of non-invasive oral carcinoma. Blocking the activity of invasion-specific MMPs or alphavbeta6 integrin might offer novel therapeutic modalities in early-stage oral carcinoma.
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PMID:Differential expression of matrilysin-1 (MMP-7), 92 kD gelatinase (MMP-9), and metalloelastase (MMP-12) in oral verrucous and squamous cell cancer. 1469 17

Rheumatoid arthritis is a chronic inflammatory disease characterized by destruction of cartilage and bone that is mediated by synovial fibroblasts. To determine the mechanisms by which these cells are activated to produce matrix metalloproteinases (MMPs), the effects of microparticles were investigated. Microparticles are small membrane-bound vesicles whose release from immune cells is increased during activation and apoptosis. Because microparticles occur abundantly in the synovial fluid in rheumatoid arthritis, they could represent novel stimulatory agents. Microparticles derived from T cells and monocytes strongly induced the synthesis of MMP-1, MMP-3, MMP-9, and MMP-13 in fibroblasts. The induction was time-dependent, with effects primarily observed after 36 h; under these conditions, MMP-2, MMP-14, and tissue inhibitor of MMP-1 (TIMP-1), TIMP-2, and TIMP-3 were not induced. Microparticles also increased the synthesis of inflammatory mediators including IL-6, IL-8, monocyte chemoattractant protein 1 (MCP-1), and MCP-2. In Ikappa-B-transfected synovial fibroblasts, MMPs were less inducible by microparticles compared with wild-type fibroblasts. Blocking of TNFalpha and IL-1beta with antibodies against TNFalpha and with IL-1 receptor antagonist did not abrogate stimulation by microparticles. These data provide evidence for a novel mechanism by which vesicles derived from activated or apoptotic immune cells can promote the destructive activity of synovial fibroblasts in rheumatoid arthritis.
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PMID:The induction of matrix metalloproteinase and cytokine expression in synovial fibroblasts stimulated with immune cell microparticles. 1570 93

Tendinopathy is accompanied by inflammation, tendon matrix degradation, or both. Inflammatory cytokine IL-1beta, which is a potent inflammatory mediator, is likely present within the tendon. The purpose of this study was to determine the biological impact of IL-1beta on tendon fibroblasts by assessing the expression of cPLA(2), COX-2, PGE(2) and its receptors (EPs), collagen type-I, and MMPs. We also studied the role of the p38 MAPK pathway in IL-1beta-induced catabolic effects. We found that IL-1beta increased the expression levels of cPLA(2) and COX-2, and also increased the secretion of PGE(2). Induction of MMPs, such as MMP-1 and MMP-3 at the mRNA level, was also observed after stimulation with IL-1beta. Furthermore, the presence of IL-1beta significantly decreased the level of collagen type-I mRNA in tendon fibroblasts. These effects were found to be mediated by selective upregulation of EP(4) receptor, which is a member of G-protein-coupled receptor that transduces the PGE(2) signal. Blocking EP(4) receptor by a specific chemical inhibitor abolished IL-1beta-induced catabolic effects. These results suggest that IL-1beta-induced catabolic action on tendon fibroblasts occurs via the upregulation of two key inflammatory mediators, cPLA(2) and COX-2, which are responsible for the synthesis of PGE(2). IL-1beta further stimulates the expression of EP(4) receptor, suggesting positive feedback regulation which may lead to accelerated catabolic processes in tendon fibroblasts. Studies using pathway-specific chemical inhibitors suggest that the p38 MAPK pathway is the key signaling cascade transducing IL-1beta-mediated catabolic effects. Collectively, our findings suggest that the EP(4) receptor mediates the IL-1beta-induced catabolic metabolism via the p38 MAPK pathway in human tendon fibroblasts and may play a major role in the tendon's degenerative changes often seen in the later stages of tendinopathy.
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PMID:EP4 receptor regulates collagen type-I, MMP-1, and MMP-3 gene expression in human tendon fibroblasts in response to IL-1 beta treatment. 1704 75

Blocking TNF effectively inhibits inflammation and structural damage in human rheumatoid arthritis (RA). However, so far it is unclear whether the effect of TNF is a direct one or indirect on up-regulation of other mediators. IL-1 may be one of these candidates because it has a central role in animal models of arthritis, and inhibition of IL-1 is used as a therapy of human RA. We removed the effects of IL-1 from a TNF-mediated inflammatory joint disease by crossing IL-1alpha and beta-deficient mice (IL-1-/-) with arthritic human TNF-transgenic (hTNFtg) mice. Development of synovial inflammation was almost unaffected on IL-1 deficiency, but bone erosion and osteoclast formation were significantly reduced in IL-1-/-hTNFtg mice, compared with hTNFtg mice based on an intrinsic differentiation defect of IL-1-deficient monocytes. Most dramatically, however, cartilage damage was absent in IL-1-/-hTNFtg mice. Chimera studies revealed that protection of cartilage is based on the loss of IL-1 on hematopoietic, but not mesenchymal, cells, leading to decreased expression of ADAMTS-5 and MMP-3. These data show that TNF-mediated cartilage damage is completely and TNF-mediated bone damage is partially dependent on IL-1, suggesting that IL-1 is a crucial mediator for inflammatory cartilage and bone degradation.
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PMID:TNF-induced structural joint damage is mediated by IL-1. 1760 89

Adult neurogenesis is regulated by both intrinsic programs and extrinsic stimuli. The enhanced proliferation of adult neural stem/progenitor cells (aNPCs) in the subventricular zone and the migration of neuroblasts toward the ischemic region in adult brains present a unique challenge as well as an opportunity to understand the molecular mechanisms underlying the extrinsic cue-induced neurogenic responses. Matrix metalloproteinases (MMPs) are a family of proteinases known to play a role in extracellular matrix remodeling and cell migration. However, their presence in aNPCs and their potential function in injury-induced aNPC migration remain largely unexplored. Here we demonstrate that in response to two injury-induced chemokines, stromal cell-derived factor 1 (SDF-1) and vascular endothelial growth factor, aNPCs differentiated into migratory cells that expressed increased levels of MMP-3 and MMP-9. Whereas differentiated neuroblasts and a subpopulation of astrocytes migrated toward the chemokines, undifferentiated progenitors did not migrate. Blocking the expression of MMP-3 or MMP-9 in aNPCs interfered with both the differentiation of aNPCs and chemokine-induced cell migration. Thus, endogenous MMPs expressed by aNPCs are important for mediating their neurogenic response to extrinsic signals.
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PMID:Endogenous matrix metalloproteinase (MMP)-3 and MMP-9 promote the differentiation and migration of adult neural progenitor cells in response to chemokines. 1881 37

Previous studies show that the chemokine CXCL16 and its receptor CXCR6 are likely to contribute to prostate cancer (PCa). In this investigation, the role of the CXCR6 receptor in PCa was further explored. CXCR6 protein expression was examined using high-density tissue microarrays and immunohistochemistry. Expression of CXCR6 showed strong epithelial staining that correlated with Gleason score. In vitro and in vivo studies in PCa cell lines suggested that alterations in CXCR6 expression were associated with invasive activities and tumor growth. In addition, CXCR6 expression was able to regulate expression of the proangiogenic factors interleukin (IL)-8 or vascular endothelial growth factor (VEGF), which are likely to participate in the regulation of tumor angiogenesis. Finally, we found that CXCL16 signaling induced the activation of Akt, p70S6K, and eukaryotic initiation factor 4E binding protein 1 included in mammalian target of rapamycin (mTOR) pathways, which are located downstream of Akt. Furthermore, rapamycin not only drastically inhibited CXCL16-induced PCa cell invasion and growth but reduced secretion of IL-8 or VEGF levels and inhibited expression of other CXCR6 targets including CD44 and matrix metalloproteinase 3 in PCa cells. Together, our data shows for the first time that the CXCR6/AKT/mTOR pathway plays a central role in the development of PCa. Blocking the CXCR6/AKT/mTOR signaling pathway may prove beneficial to prevent metastasis and provide a more effective therapeutic strategy for PCa.
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PMID:CXCR6 induces prostate cancer progression by the AKT/mammalian target of rapamycin signaling pathway. 1907 6


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