Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.3 (collagenase)
 18,340 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Serum levels of matrix metalloprotease-9 (MMP-9) and tissue inhibitor of MMP-1 (TIMP-1) were measured monthly in 7 patients with relapsing-remitting multiple sclerosis (MS) 6 months before and 6 months during treatment with weekly intramuscular (i.m.) injections of interferon-beta1a (IFN-beta1a) 30 microg. Within-patient median MMP-9 levels were unchanged on treatment. Within-patient median TIMP-1 levels were higher during months 1-6 (771.5 ng/ml) and during months 4, 5, and 6 of treatment (793 ng/ml) compared with 6 months pretreatment (414 ng/ml) (respectively, p = 0.10, p = 0.047; Wilcoxon signed-rank test). These preliminary data suggest that IFN-beta1a therapy may increase TIMP-1 levels.
J Interferon Cytokine Res 2001 Mar
PMID:IFN-beta1a may increase serum levels of TIMP-1 in patients with relapsing-remitting multiple sclerosis. 1133 Oct 41

We have previously demonstrated that interferon-alpha2b (IFN-alpha2b) markedly depresses the expression of mRNA for type I procollagen in dermal fibroblasts. In the present study, the effect of various concentrations of IFN-alpha2b on the expression of collagenase mRNA and activity of 5'-flanking regions of collagenase promoter in dermal fibroblasts are presented. The results showed at least a 2-fold increase in the expression of collagenase mRNA in fibroblasts grown at either 70% confluency (40.9 +/- 4.6 vs. 18.5 +/- 1.6, n=4, p<0.05) or 95% confluency (24.7 +/- 6.7 vs. 4.5 +/- 1.6, n=4, p<0.05). The effects of IFN-alpha2b on collagenase mRNA stability and promoter activity were evaluated to determine the mechanism by which IFN-alpha2b increases the expression of collagenase mRNA. IFN-alpha2b-treated and untreated fibroblasts were treated with alpha-amanitin to arrest collagenase mRNA transcription, and total RNA was then harvested at 0, 3, 6, 12, and 24 h. The decay curves of collagenase mRNA as a function of time showed a greater rate of degradation for collagenase mRNA in IFN-alpha2b-treated cells relative to untreated control cells. This difference was more pronounced in cells treated with alpha-amanitin at either 12 or 24 h. To determine the regions of the collagenase promoter that might function as IFN-alpha2b responsive elements, eight different fragments of the collagenase promoter, -518, -300, -171, -161, -127, -91, -74, and -66 to +63 nucleotide (nt), were constructed in a chloramphenicol acetyltransferase (CAT) expression vector. The results of CAT activity of cells transfected with these construct identified three constructs, 171/+63, -161/+63, and -127/+63, as being responsive to IFN-alpha2b treatment in dermal fibroblasts. The CAT activity was increased 279%, 163%, and 261% in -171/+63, -161/+63, and -127/+63-transfected fibroblasts, respectively, in response to IFN-alpha2b treatment relative to untreated control. No significant increase in CAT activity was found in cells transfected with the other constructs of the collagenase promoter. A time response experiment showed a marked increase in CAT activity of cells transfected with either 127/+63 or -171/63 constructs within 6-12 hr of IFN-alpha2b treatment. In conclusion, IFN-alpha2b significantly increases the expression of collagenase mRNA in dermal fibroblasts probably through stimulation of the -127/-91 region of the collagenase promoter. Thus, this region may function as an IFN-alpha2b responsive element on collagenase promoter.
J Interferon Cytokine Res 2001 Aug
PMID:Induction of collagenase mRNA expression in dermal fibroblasts by IFN-alpha 2b and determination of the IFN-alpha 2b responsive element on 5'-flanking regions of collagenase promoter. 1155 39

Tumour necrosis factor-alpha (TNF-alpha) was able to promote collagen breakdown from bovine cartilage in explant culture. This release was dependent upon matrix metalloproteinases (MMPs) and could be prevented by transforming growth factor-beta1 (TGF-beta1) or insulin-like growth factor-1. Both growth factors reduced the expression and secretion of collagenase enzymes, and TGF-beta1 induced tissue inhibitor of metalloproteinase production. This study shows for the first time that these anabolic growth factors can protect cartilage against TNF-alpha-induced destruction.
Cytokine 2001 Oct 07
PMID:Modulation of the expression of matrix metalloproteinase and tissue inhibitors of metalloproteinases by TGF-beta1 and IGF-1 in primary human articular and bovine nasal chondrocytes stimulated with TNF-alpha. 1166 84

Hand function depends on tendon integrity, but in rheumatoid arthritis tenosynovitis can result in tendon adhesions and rupture. Cytokine inhibitors have proved effective in rheumatoid joint disease; however, their effect on the tenosynovium is not well understood. We investigated the ability of inhibitors of tumour necrosis factor alpha and interleukin 1 to reduce production of collagenolytic matrix metalloproteinases 1 and 13 in tenosynovial tissue obtained from patients with rheumatoid arthritis. Our data show that cytokine blockade can reduce collagenase concentrations in tenosynovial tissue, suggesting cytokine inhibitors could be effective in reduction of tendon damage.
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PMID:Treatment of rheumatoid tenosynovitis with cytokine inhibitors. 1244 96

Cell and tissue therapy applications in humans are being used increasingly, particularly for tissue repair. Several reconstructed skin models have been proposed. Wound healing involves overlapping steps of inflammation, cell migration and proliferation, neovascularisation, extracellular matrix production and remodelling. This is regulated by numerous cytokines and other soluble mediators. We have prepared dermal substitutes (DS) consisting of a collagen-GAG, three-dimensional matrix colonized by human dermal fibroblasts (HDF), isolated by skin explant or enzymatic digestion of the skin for potential therapeutic use in humans. To test the functionality of these DS, we measured (ELISA) the stimulatory effect on HDF in the matrix, of serial dilutions of human serum (HS) on the production of wound healing mediators: interleukin-8 (IL-8), vascular endothelial growth factor (VEGF), keratinocyte growth factor (KGF) and tissue inhibitor of metalloproteinase-1 (TIMP-1). We observed: 1). a stimulatory effect of HS on HDF production of the different mediators tested, with a dose-dependent effect in the case of IL-8 and VEGF. 2). A matrix-potentiating effect on the production of the different mediators by HDF. 3). A decrease in the production of IL-8 and VEGF when HDF isolated by enzymatic digestion was used to colonize the matrix as compared with HDF isolated by skin explant. We conclude: 1). that the production by HDF, in a collagen-GAG matrix, of mediators involved in cutaneous wound healing is decreased when HDF are isolated by enzymatic skin digestion rather than by skin explant. 2). That measurement of the production of cytokines or other mediators could be a useful quality control to test the functionality of tissue-engineered DS for tissue repair therapy in humans and more generally of cells prepared for cell therapy.
Eur Cytokine Netw
PMID:Wound healing mediator production by human dermal fibroblasts grown within a collagen-GAG matrix for skin repair in humans. 1279 15

Epidermolysis bullosa acquisita (EBA) is a chronic, uncommon, sub-epidermal blistering disease involving the skin and mucous membranes that heals with scar formation and milia. Collagens, matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) are important components that play an essential role(s) in matrix remodeling during scar formation. However, the possible involvement of these components in EBA-induced scarring is not yet known. In the present study, we examined the expression profile of collagens, collagen-binding heat shock protein 47 (HSP47), MMPs and their inhibitory enzymes, TIMPs, in matrix remodeling during conjunctival scarring. The involvement of TGF-beta1, a fibrogenic factor, was also studied. Compared to the controls, an increased expression of type I collagen, type III collagen and HSP47 was detected in conjunctival biopsy sections of patient with EBA using immunohistochemistry. Similar increase in the expression of type I collagen, type III collagen and HSP47 was noted in conjunctival fibroblasts obtained from the patient with EBA. Up-regulation in the expression of MMP-1 and MMP-14 was also noted in conjunctival fibroblasts isolated from the patient with EBA, while no significant changes in the expression of MMP-3, MMP-8, MMP-9 and MMP-13 were seen. As for TIMPs, conjunctival fibroblasts isolated from the patient with EBA, grown in vitro, exhibited increased expression of TIMP-1, TIMP-2 and TIMP-3, when compared with fibroblasts grown from control conjunctival tissues, although the expression level varies with different molecules of the same family. Additionally, compared to the control conjunctival fibroblasts, an increased expression of TGF-beta1 was detected in fibroblasts isolated from the conjunctival tissues of patient with EBA. This study suggests that there is up-regulation in the production of collagens (type I and III), collagen-binding protein (HSP47), matrix degrading collagenases (MMP-1 and 14), and their inhibitory enzymes (TIMP-1, 2 and 3) during the process of conjunctival matrix remodeling in the patient with EBA. The presented data is preliminary and could serve as a basis for further studies to enhance our understanding about the molecular mechanisms of conjunctival scarring in patients with EBA.
Cytokine 2003 Mar 07
PMID:Expression profiles of collagens, HSP47, TGF-beta1, MMPs and TIMPs in epidermolysis bullosa acquisita. 1282 5

Decorin is a small leucine-rich proteoglycan that plays a role in control of cell proliferation, cell migration, collagen fibrillogenesis and modulation of the activity of TGF-beta. In the present study, we investigated the effects of decorin on the production of metalloproteinases (MMP-1, -2, -3, -9 and -13), tissue inhibitors of metalloproteinases (TIMP-1, -2) and cytokines (TGF-beta, IL-1beta, IL-4 and TNF-alpha). Decorin was overexpressed in cultured human gingival fibroblasts using adenovirus-mediated gene transfer. Decorin infection resulted in decreased protein levels of MMP-1 and MMP-3 whereas MMP-2 and TIMP-2 secretion was increased. MMP-9, MMP-13 and TIMP-1 were not affected by decorin infection. Cytokine measurements by ELISA showed that decorin overexpression reduced TGF-beta and IL-1beta. In contrast, IL-4 and TNF-alpha levels were markedly increased in decorin-infected cells. These results suggest that decorin could modulate the expression of certain metalloproteinases and their inhibitors, as well as the production of cytokines. Altogether, our data suggest that decorin might play a pivotal role in tissue remodeling by acting on the balance between extracellular matrix synthesis and degradation.
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PMID:Effect of adenovirus-mediated overexpression of decorin on metalloproteinases, tissue inhibitors of metalloproteinases and cytokines secretion by human gingival fibroblasts. 1285 35

Chronic hypoxia is implicated in lung fibrosis, which is characterized by enhanced deposition of extracellular matrix (ECM) molecules. Transforming growth factor-beta (TGF-beta) plays a key role in fibroblast homeostasis and is involved in disease states characterized by excessive fibrosis, such as pulmonary fibrosis. In this study, we investigated if hypoxia modulates the effects of TGF-beta on the expression of gelatinases: matrix metalloproteinase (MMP)-2 and MMP-9, interstitial collagenases: MMP-1 and MMP-13, tissue inhibitors of MMP (TIMP), collagen type I and interleukin-6 (IL-6). Primary human lung fibroblasts, established from tissue biopsies, were cultivated under normoxia or hypoxia in the presence of TGF-beta1, TGF-beta2 or TGF-beta3. Gelatinases were assessed by gelatin zymography and collagenases, TIMP, collagen type I and IL-6 by ELISA. Under normoxia fibroblasts secreted MMP-2, collagenases, TIMP, collagen type I and IL-6. TGF-betas significantly decreased MMP-1 and increased TIMP-1, IL-6 and collagen type I. Hypoxia significantly enhanced MMP-2, and collagenases. Compared to normoxia, the combination of TGF-beta and hypoxia reduced MMP-1, and further amplified the level of TIMP, IL-6, and collagen type I. Thus, in human lung fibroblasts hypoxia significantly increases the TGF-betas-induced secretion of collagen type I and may be associated to the accumulation of ECM observed in lung fibrosis.
Cytokine 2003 Oct
PMID:Hypoxia modulates the effects of transforming growth factor-beta isoforms on matrix-formation by primary human lung fibroblasts. 1456 88

Interleukin-1 (IL-1) plays a crucial role in the immunopathological responses involved with tissue destruction in chronic inflammatory diseases, such as periodontal disease, as it stimulates host cells including fibroblasts to produce various inflammatory mediators and catabolic factors. We comprehensively investigated the involvement of mitogen-activated protein kinases (MAPKs)/activator protein-1 (AP-1) and IkappaB kinases (IKKs)/IkappaBs/nuclear factor-kappaB (NF-kappaB) in IL-1beta-stimulated IL-6, IL-8, prostaglandin E(2) (PGE(2)) and matrix metalloproteinase-1 (MMP-1) production by human gingival fibroblasts (HGF). Three MAPKs, extracellular signal-regulated kinase (ERK), p38 MAPK and c-Jun N-terminal kinase (JNK), which were simultaneously activated by IL-1beta, mediated subsequent c-fos and c-jun mRNA expression and DNA binding of AP-1 at different magnitudes. IKKalpha/beta/IkappaB-alpha/NF-kappaB was also involved in the IL-1 signaling cascade. Further, IL-1beta stimulated HGF to produce IL-6, IL-8, PGE(2) and MMP-1 via activation of the 3 MAPKs and NF-kappaB, as inhibitors of each MAPK and NF-kappaB significantly suppressed the production of IL-1beta-stimulated factors, though these pathways might also play distinct roles in IL-1beta activities. Our results strongly suggest that the MAPKs/AP-1 and IKK/IkappaB/NF-kappaB cascades cooperatively mediate the IL-1beta-stimulated synthesis of IL-6, IL-8, PGE(2) and MMP-1 in HGF.
Cytokine 2005 Feb 21
PMID:Interleukin-1 stimulates cytokines, prostaglandin E2 and matrix metalloproteinase-1 production via activation of MAPK/AP-1 and NF-kappaB in human gingival fibroblasts. 1565 48

The small GTPases of the Rho family are key intermediates in cellular signalling triggered by activated cell-adhesion receptors. In this study, we took advantage of RNA interference (RNAi) using small interfering RNAs (siRNAs) to define the roles of the best-characterized members of the RhoGTPase family, RhoA, Rac1 and Cdc42, in the control of MMP-1, MMP-2 and type-I-collagen expression in normal human skin fibroblasts (HSFs). A specific and long-lasting repression, up to 7 days after transfection, of the three GTPases was achieved by transient transfection of specific siRNA. The silencing of Cdc42, but not that of RhoA or Rac1, induced a 15-fold increase in MMP-1 secretion. This upregulation was confirmed at the mRNA level and observed with two different siRNAs targeting Cdc42. Such a regulation was also observed in various human cell lines and was rescued by re-expressing wild-type Cdc42 encoded by a construct bearing silent mutations impeding its recognition by the siRNA. By contrast, MMP-2 and type-I-collagen expression was not affected by the individual silencing of each Rho GTPase. Cytokine protein array, enzyme-linked immunosorbent assays and reverse-transcription PCR measurements revealed that ablation of Cdc42 induced an overexpression of interleukin 8 and MCP-1. Although these cytokines are known to induce the expression of MMP-1, we showed that they were not involved in the Cdc42-mediated upregulation of MMP-1. Silencing of Cdc42 also induced an increased phosphorylation of ERK1/2 and p38 MAP kinase. The use of chemical inhibitors on Cdc42-ablated cells revealed that the upregulation of MMP-1 is dependent on the ERK1/2 pathways, whereas the p38 MAP kinase pathway displayed an inhibitory role. Simultaneous knock-down of two or three Rho GTPases allowed us to demonstrate that the RhoA-ROCK pathway was not involved in this regulation but that the silencing of Rac1 reduced the effect of Cdc42 suppression. These data suggest that, in vivo, when cell/extracellular-matrix interactions via integrins induce cytoskeleton organization, MMP-1 expression is maintained at a low level by Cdc42 via a repression of the Rac1 and ERK1/2 pathways. Therefore, Cdc42 contributes to ECM homeostasis and connective tissue integrity.
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PMID:Cdc42 downregulates MMP-1 expression by inhibiting the ERK1/2 pathway. 1572 53


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