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

The basal levels of mRNAs encoding two metalloproteinases, collagenase and stromelysin, were increased as a function of in vitro serial subcultivation (cellular aging) of human fibroblasts. Procollagenase and prostromelysin synthesis and secretion were also greater in the old cultures (late passage). In contrast, the steady-state expression of mRNA for an inhibitor of metalloproteinases, tissue inhibitor of metalloproteinase-1 (TIMP-1), in late-passage cultures was lower than that in young cell cultures (early passage). Each mRNA was analyzed using total RNA preparations isolated from normal fibroblast cultures at different phases of the in vitro life span and from cultures derived from donors with the premature senescence syndromes characterized as Werner syndrome, progeria (Hutchinson-Gilford) syndrome, or Cockayne syndrome. In normal cell cultures expression of metalloproteinase mRNAs was increased after the culture had completed greater than 90% of the in vitro life span, and the reduction in TIMP-1 mRNA expression occurred after the culture had completed greater than 74% of the in vitro lifespan. In Werner syndrome cultures expression of metalloproteinase and TIMP-1 mRNAs was similar to the level of expression observed in late-passage cell cultures. Levels of metalloproteinase and TIMP-1 mRNA expression in progeria and Cockayne syndromes were similar to those of early-passage cell cultures. To determine if young and old cells were each responsive to mediators of metalloproteinase synthesis, cultures were treated with phorbol ester or cytokines. 12-O-tetradecanoylphorbol-13-acetate treatment increased the steady-state levels of all three mRNAs in young, old, and Werner syndrome cultures and increased procollagenase levels in all cultures. Early- and late-passage cell cultures also responded to cytokines. Interleukin-1 alpha treatment increased collagenase and stromelysin mRNA levels while transforming growth factor-beta reduced the steady-state levels of both transcripts. Neither cytokine affected the steady-state level of TIMP-1 mRNA. The results indicate that in vitro cellular aging is associated with changes in expression of mRNAs encoding proteins that mediate inflammatory responses and connective tissue remodeling.
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PMID:Differential expression of metalloproteinase and tissue inhibitor of metalloproteinase genes in aged human fibroblasts. 132 16

Expression of the rat stromelysin (transin) gene is stimulated by growth factors such as epidermal growth factor (EGF) and platelet-derived growth factor (PDGF), and inhibited by transforming growth factor-beta (TGF beta). Stimulation by both EGF and PDGF requires the presence of factors that recognize the AP-1 binding site in the stromelysin promoter, but PDGF stimulation requires induction of the protooncogene c-fos, while EGF acts through a FOS-independent pathway. The FOS-independent pathway appears to involve protein kinase C (PKC), since EGF, but not PDGF, requires activated protein kinase C to stimulate stromelysin expression. TGF beta inhibition of stromelysin gene expression requires an upstream sequence, referred to as the TGF beta inhibitory element (TIE). FOS is also a part of a protein complex that binds to the TIE. The protooncogene FOS is therefore involved in both stimulation and inhibition of stromelysin gene expression.
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PMID:The role of C-Fos in growth factor regulation of stromelysin/transin gene expression. 148 19

To understand better the molecular nature of the epithelial-mesenchymal interactions that govern folliculogenesis and hair growth, we have studied the behavior of cultured rat dermal papilla cells (rDP), the mesenchymal component of the hair follicle. Basic fibroblast growth factor (bFGF) and platelet-derived growth factor (PDGF) both potentiated the growth of rDP in culture, and transforming growth factor-beta (TGF-beta) inhibited rDP proliferation. Biosynthetic labeling studies demonstrated that both PDGF and bFGF induced synthesis of a major secreted protein(s) with Mr = 55-60 kD. It was noted that PDGF and bFGF differentially regulated synthesis of this major secreted protein; PDGF-mediated induction was found to be transient, while bFGF allowed prolonged synthesis of the protein. Sodium dodecyl sulfate (SDS)-substrate gel analysis of rDP-conditioned media revealed that this protein is a metalloproteinase with casienolytic activity and Mr approximately 51 kD (unreduced). We have identified the growth factor-regulated rDP protein as the matrix metalloproteinase stromelysin by immunoprecipitation. Northern analysis established that increased secretion of stromelysin was accompanied by an increased expression of stromelysin-specific mRNA. Remarkably, stromelysin antisera interfere with stimulation of dermal papilla cell growth, demonstrating that stromelysin production serves a functional role in mitogen-induced proliferation in these cells. These findings provide insight into the mechanism by which the connective tissue remodeling required for formation of hair embryonically and the postembryonic hair cycle may be regulated.
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PMID:Secretion of stromelysin by cultured dermal papilla cells: differential regulation by growth factors and functional role in mitogen-induced cell proliferation. 156 47

Interleukin-1 (IL-1) plays an important role in cartilage destruction associated with inflammatory and degenerative arthritis because of its ability to induce matrix degrading enzymes. Previously, we have shown that the IL-1-induced chondrocyte protease activity was inhibited by transforming growth factor-beta (TGF-beta). In this paper, we show that TGF-beta inhibits the IL-1-induced synthesis of collagenase and stromelysin by reducing the steady-state mRNA levels in rabbit articular chondrocytes. We further demonstrate that TGF-beta-treated chondrocytes show reduced 125I-IL-1 binding that returns to a normal level when TGF-beta is removed from the culture medium. The inhibitory effect of TGF-beta is observed for both naturally occurring as well as fibroblast growth factor (FGF)-inducible binding sites (receptors). Scatchard analysis of receptor-ligand interactions demonstrate that the reduced binding is due to a reduction in the number of receptors for IL-1 and is not due to changes in affinity. Affinity cross-linking studies suggest that control chondrocytes contain two major cross-linked bands of Mr = 116 and 80 kDa and a minor band of Mr = 100 kDa. FGF-treated cells show enhanced levels of all the bands, plus an additional 200-kDa band. TGF-beta treatment of chondrocytes results in the reduction of all of these bands in both control as well as FGF-induced cells. These observations suggest that the ability of TGF-beta to down-regulate the IL-1 receptor may be a mechanism by which it exerts its effects in antagonizing the IL-1 activity on chondrocytes.
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PMID:Transforming growth factor-beta inhibition of interleukin-1 activity involves down-regulation of interleukin-1 receptors on chondrocytes. 164 57

The enzyme collagenase participates in remodeling the extracellular matrix of corneal stroma during normal wound healing and mediates the degradation of extracellular matrix that occurs in many corneal pathologic states. Because this enzyme is synthesized and secreted by corneal cells, therapy of degradative disorders might be geared toward control of enzyme expression. The effects of two cytokines, transforming growth factor-beta (TGF-beta) and interleukin-1 (IL-1), on the expression of collagenase by cultured corneal stromal cells are reported. In addition, the concomitant effects of these cytokines on expression of three additional members of the matrix metalloproteinase (MMP) family--stromelysin, 72-kilodalton (kD) gelatinase, and 92-kD gelatinase--were investigated. When stromal cells are situated in the normal corneal stroma, they produce only a single MMP, 72-kD gelatinase. This pattern of expression was reproduced by stromal cells freshly plated in primary culture. However after passage in culture, the cells also began to secrete collagenase and stromelysin. Treatment of primary cultures with recombinant human IL-1 also induced collagenase and stromelysin expression. In addition, 92-kD gelatinase expression was induced and 72-kD gelatinase expression was increased further by IL-1 treatment. Treatment of passaged cultures or IL-1-treated primary cultures with recombinant human TGF-beta reverted the pattern of enzyme expression toward that exhibited by primary, untreated cultures, ie, expression of collagenase and stromelysin was repressed while expression of 72-kD gelatinase was increased. These results suggest that TGF-beta and IL-1 may be important agents for controlling MMP expression in healthy and diseased corneas.
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PMID:Transforming growth factor-beta and interleukin-1 modulate metalloproteinase expression by corneal stromal cells. 165 Dec 96

Endothelial cells play a fundamental role in the pathogenesis of chronic inflammatory arthritis in humans such as rheumatoid arthritis (RA), as well as experimental animal models such as streptococcal cell wall (SCW) arthritis in Lewis (LEW/N) rats. This review summarizes data in support of this concept. The earliest apparent abnormalities in synovial tissues of patients with RA and Lewis rats with SCW arthritis appear to reflect microvascular endothelial cell activation or injury. At the molecular level, the abnormalities include enhanced expression by endothelial cells of activation markers such as class II major histocompatibility complex antigens, phosphotyrosine, leukocyte adhesion molecules, oncoproteins such as c-Fos and c-Myc, and metalloproteinases such as collagenase and transin/stromelysin. The development of severe, chronic, destructive arthritis is dependent upon thymic-derived lymphocytes and is accompanied by tumorlike proliferation of cells in the synovial connective tissue stroma (blood vessels and fibroblastlike cells), which results in resorptive destruction of bone and cartilage. Multiple criteria support the analogy to a neoplastic process. Paracrine and autocrine factors such as interleukin-1 (IL-1), platelet-derived growth factor (PDGF), transforming growth factor-beta (TGF-beta), and heparin-binding fibroblast growth factors (HBGF, FGF) appear to play important roles in the generation of these lesions. Finally, in addition to the autocrine and paracrine regulatory factors, neuroendocrine factors, particularly the hypothalamic-pituitary-adrenal axis, appear to be involved in the counterregulation of the inflammatory process. The counterregulatory effects are mediated, in part, by inhibition of endothelial cell activation by corticosteroids.
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PMID:Endothelial cells and the pathogenesis of rheumatoid arthritis in humans and streptococcal cell wall arthritis in Lewis rats. 205 44

Transin is an oncogene-inducible protein which has been shown to be the rat homologue of an extracellular matrix-degrading metalloproteinase known as stromelysin. The activity of transin/stromelysin is regulated at several levels: (1) at the transcriptional level, it is positively regulated by oncogenes, tumor promoters, and certain growth factors, and is negatively regulated by several agents including glucocorticoids and transforming growth factor-beta; (2) the protease activity is produced by processing of an inactive precursor form to an active enzyme; and (3) total protease activity is modulated by activity of tissue inhibitors of metalloproteinases (TIMPs). The association of transin/stromelysin expression with tumor progression suggests that it plays an important role in cancer.
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PMID:Stromelysin/transin and tumor progression. 210 88

Stromelysin-1 and collagenase mRNA levels were assayed in fibrochondrocytes by Northern blot analysis at 0, 2, 4, 8 and 24 h after stimulation with tissue necrosis factor-alpha (TNF-alpha). Peak collagenase mRNA levels occurred 24 h after stimulation and were increased nine-fold over the level at time 0. Stromelysin-1 mRNA levels peaked 8 h after stimulation, with a five-fold increase over the level at time 0. A TNF-alpha dose-related response to both collagenase and stromelysin-1 mRNA accumulation was also demonstrated. Confirmation of the presence of secreted metallo-proteinases in the conditioned media was established by immunoprecipitation of stromelysin-1 and Western blotting of collagenase. Both enzymes were secreted in latent forms. Consistent with stromelysin-1 activity, substrate gels demonstrated a doublet of caseinase activity with molecular masses at 57 kDa and 59 kDa in TNF-alpha stimulated samples. Collagenase assays of conditioned media also demonstrated a significant increase in collagenase activity after stimulation by TNF-alpha. While epidermal growth factor had a minimal effect on stromelysin-1 and collagenase expression, transforming growth factor-beta, and insulin-like growth factor-1 did not induce either enzyme activity.
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PMID:Induction of stromelysin-1 and collagenase synthesis in fibrochondrocytes by tumor necrosis factor-alpha. 792 41

Various forms of nephropathy accompany interstitial fibrosis with lymphocytic infiltration. To probe the relationship between lymphocyte-derived factors and renal fibroblasts, we studied the effect of culture supernatant from lymphocytes stimulated by concanavalin A (ConASN) on the growth and matrix metabolism of rat kidney fibroblasts. 3H-thymidine incorporation and Northern analysis, respectively, revealed that ConASN repressed cell growth and the mRNA level of collagen type I, but dramatically elevated the steady-state expression of metalloproteinase transin/stromelysin. The growth inhibitor in ConASN was moderately heat-sensitive and less than 5 kD in molecular size, qualities that differed from those of transforming growth factor-beta (TGF-beta), IL-1 beta, IL-6, and tumour necrosis factor-alpha (TNF-alpha). The matrix regulatory factor in ConASN was highly heat-sensitive and more than 30 kD in size. Among several lymphokines tested, TNF-alpha produced the same effects as ConASN on the metabolism of extracellular matrix. We hypothesize that lymphocyte-derived factors have a significant role in the attenuation of renal fibrogenesis, as well as its progression, via inhibiting cell growth and matrix accumulation.
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PMID:Renal fibroblasts are sensitive to growth-repressing and matrix-reducing factors from activated lymphocytes. 844 72

A temperature-dependent metastatic phenotype reported for a frog cell line, PNKT-4B, provided a means for studying potential mediators of cell-matrix interaction involved in metastatic invasion. Zymography revealed that these cells secreted enzyme species with properties and characteristics of mammalian metalloproteinases: collagenase, stromelysin, gelatinase A, and gelatinase B. These enzymes were produced by PNKT-4B cultures maintained at both invasive-permissive (28 degrees C), and invasion-restrictive (20 degrees C) temperatures. However, under the invasive-permissive culture condition cells produced more of the putative gelatinase B and A enzymes. In addition, an activated form of gelatinase A was produced only in invasion-permissive cultures. DNA synthesis bioassays (Mv1Lu cell line and mouse thymocytes) to detect growth promoting and/or inhibitory cytokines, revealed that PNKT-4B cultures kept at 28 degrees C released significantly higher levels of stimulatory (interleukin-1-like) and latent inhibitory (transforming growth factor-beta-like) substances into the medium compared to 20 degrees C cultures. Pre-absorption of media samples with heparin-sepharose indicated a second stimulatory cytokine as well. A corneal fibroblast bioassay that tests for mediators of collagenase synthesis, detected a stimulatory substance whose activity was greatly reduced in the presence of interleukin-1 receptor antagonist protein. Collagenase stimulatory activity present in 28 degrees C culture medium was significantly higher than equal samples from 20 degrees C cultures. These studies provide a molecular correlation between release of cytokines with properties of the metastatic phenotype seen in vivo. They further provide some of the first characterizations of frog MMPs and cytokines, which are likely to be involved in other tissue remodeling events.
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PMID:Frog PNKT-4B cells express specific extracellular matrix-degrading enzymes and cytokines correlated with an invasive phenotype. 920 30


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