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)

The constitutive secretion of latent TGF-beta by many cell types in culture suggests that extracellular mechanisms to control the activity of this potent cytokine are important in the pathogenesis of the diseases in which this cytokine may be involved, including fibrotic disorders. In this study, we focused on the alpha(v)beta3 integrin, which is recently demonstrated to function as an active receptor for latent TGF-beta1 through its interaction with latency-associated peptide-beta1, and investigated the involvement of this integrin in the pathogenesis of scleroderma. Scleroderma fibroblasts exhibited increased alpha(v)beta3 expression compared with normal fibroblasts in vivo and in vitro. In scleroderma fibroblasts, ERK pathway was constitutively activated and such abnormality induced the up-regulation of alpha(v)beta3. Transient overexpression of alpha(v)beta3 in normal fibroblasts induced the increase in the promoter activity of human alpha2(I) collagen gene and the decrease in that of human MMP-1 gene. These effects of alpha(v)beta3 were almost completely abolished by the treatment with anti-TGF-beta Ab or TGF-beta1 antisense oligonucleotide. Furthermore, the addition of anti-alpha(v)beta3) Ab reversed the expression of type I procollagen protein and MMP-1 protein, the promoter activity of human alpha2(I) collagen gene, and the myofibroblastic phenotype in scleroderma fibroblasts. These results suggest that the up-regulated expression of alpha(v)beta3 contributes to the establishment of autocrine TGF-beta loop in scleroderma fibroblasts, and this integrin is a potent target for the treatment of scleroderma.
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PMID:Increased expression of integrin alpha(v)beta3 contributes to the establishment of autocrine TGF-beta signaling in scleroderma fibroblasts. 1630 81

In previous studies we found that Morinda citrifolia (Noni) fruit extract up-regulated biosynthesis of type I collagen and glycosaminoglycans in primary cultures of normal human fibroblasts. The objective of this study was to identify the active ingredients in Noni fruit extract. An active single compound having a type I collagen-stimulating effect was isolated and identified as 1,4-dihydroxy-2-methoxy-7-methylanthraquinone by nuclear magnetic resonance, infrared, and mass analysis. It was revealed that anthraquinone showed significantly increased elaboration of procollagen type I C-terminal peptide and glycosaminoglycans and reduced expression of the collagenase matrix metalloproteinase-1 dose-dependently in human dermal fibroblasts. Furthermore, in a clinical trial, a nano-emulsion containing anthraquinone predominantly increased the dermal type I procollagen in nude mouse skin. These results suggest that anthraquinone derived from Noni extract is a good candidate for use as a new anti-wrinkle agent due to its strong induction of biosynthetic activity of extracellular matrix components.
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PMID:Induction of extracellular matrix synthesis in normal human fibroblasts by anthraquinone isolated from Morinda citrifolia (Noni) fruit. 1637 72

EGF and type I collagen are known to play important roles in wound healing. In the present study, we demonstrated that EGF down-regulates the expression of type I procollagen protein as well as alpha2(I) collagen mRNA in cultured human dermal fibroblasts. EGF induced the degradation of type I procollagen protein in conditioned medium through the up-regulation of MMP-1 expression. EGF down-regulated alpha2(I) mRNA expression partially at the post-transcriptional level by reducing the mRNA stability. In contrast, EGF up-regulated MMP-1 mRNA expression mostly at the transcriptional level, in that it had a stimulatory effect on MMP-1 promoter activity, but no effect on MMP-1 mRNA stability. The MEK/ERK signaling pathway was shown to be involved in EGF-mediated type I collagen and MMP-1 expression.
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PMID:Epidermal growth factor affects the synthesis and degradation of type I collagen in cultured human dermal fibroblasts. 1641 67

Localized scleroderma (LSc) is a connective tissue disorder limited to skin and subcutaneous tissue, which may share pathogenic processes with systemic sclerosis (SSc). We previously demonstrated that upregulated expression of integrin alphavbeta5 might contribute to autocrine TGF-beta signaling in SSc fibroblasts. Based on these data, we presently focused on alphavbeta5 and assessed its involvement in pathogenesis of LSc. We initially demonstrated that LSc fibroblasts might be activated by the stimulation of autocrine TGF-beta. Consistent with SSc fibroblasts, expression levels of alphavbeta5 were elevated in LSc fibroblasts in vitro and in vivo. Anti-alphavbeta5 antibody partially reversed expression levels of type I procollagen and MMP-1 and constitutive DNA-Smad3 binding in LSc fibroblasts. In LSc fibroblasts pretreated with antisense TGF-beta1, exogenous latent TGF-beta1 stimulation increased expression of type I procollagen in an alphavbeta5-dependent manner. The luciferase activities of TMLC cells, Mv1Lu cells stably expressing a portion of the plasminogen activator inhibitor 1 promoter, co-cultured with LSc fibroblasts were significantly elevated compared with those co-cultured with normal fibroblasts and were significantly reduced in the presence of anti-alphavbeta5 antibody. Anti-alphavbeta5 antibody reversed the myofibroblastic features of LSc fibroblasts. These results indicate that upregulated expression of alphavbeta5 contributes to autocrine TGF-beta signaling in LSc fibroblasts.
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PMID:Involvement of alphavbeta5 integrin in the establishment of autocrine TGF-beta signaling in dermal fibroblasts derived from localized scleroderma. 1667 63

Alterations of human skin connective tissue structure and function are prominent features of chronological aging and solar UV irradiation-induced premature aging (photoaging). These skin connective tissue abnormalities result, in part, from reduced synthesis and elevated degradation of type I collagen, the major structural protein in skin. Here, we report that cysteine-rich 61 (CYR61/CCN1), a novel mediator of collagen homeostasis, is predominantly expressed in human skin connective tissue and is significantly elevated in fibroblasts in chronologically aged (80+ years) and photoaged human skin in vivo. In cultured human skin fibroblasts, elevated CYR61 expression substantially reduces type I procollagen and concurrently increases matrix metalloproteinase-1 (MMP-1), which initiates fibrillar collagen degradation. Elevated CYR61 caused down-regulation of transforming growth factor-beta type II receptor mRNA and protein levels, thereby impairing the transforming growth factor-beta pathway, which reduced type I procollagen and raised MMP-1 expression. Furthermore, elevated CYR61 induced transcription factor activator protein-1 (AP-1), which functions to stimulate MMP-1 expression. Thus, elevated expression of CYR61 in human skin fibroblasts acts through multiple pathways to cause alterations of collagen homeostasis similar to those pathways observed in aged human skin in vivo. These data identify CYR61 as a pivotal regulator of collagen production and degradation in aged and photoaged human skin.
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PMID:Elevated cysteine-rich 61 mediates aberrant collagen homeostasis in chronologically aged and photoaged human skin. 1687 50

Human skin is daily exposed to infrared (IR) radiation from natural sunlight. However, the effects of IR irradiation on collagen metabolism have not been investigated in human skin in vivo. Here, we examined whether single or repeated (three times a week for 4 weeks) exposure to IR irradiation changes the expressions of type I procollagen and interstitial collagenase (MMP-1). By using immunostaining, Western blotting, and semi-quantitative RT-PCR, we analyzed the protein and mRNA levels of type I procollagen and MMP-1 in young buttock skin. A single dose of IR to human skin increased the expression of type I procollagen within 24h, but did not change the expression of MMP-1. On the other hand, multiple IR doses reduced the expression of type I procollagen and increased the expression of MMP-1. We also found that TGF-betas may mediate type I procollagen synthesis in IR-irradiated human skin. Our results demonstrate that the regulations of the expressions of type I procollagen and MMP-1 differ in acute and chronically IR-irradiated skin. In particular, decreased collagen levels and increased MMP-1 levels in chronic IR-irradiated skin may be associated with connective tissue damage. Thus, we suggest that repeated exposure to IR irradiation might induce premature skin aging (photoaging) in human skin in vivo.
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PMID:Regulation of type I procollagen and MMP-1 expression after single or repeated exposure to infrared radiation in human skin. 1706 54

We have recently shown that both interferon gamma (gamma) and interferon alpha-2b (alpha-2b) markedly depress the expression of messenger RNA for type I procollagen and fibronectin in postburn hypertrophic scar and normal dermal fibroblasts. In this article we examine the effects of these cytokines on the expression of mRNA for collagenase and its natural inhibitor, tissue inhibitor of metalloproteinase-1. Twelve different fibroblast cell strains, six from postburn hypertrophic scar and six from the normal dermis of the same patients, were established in cell culture. The results of a dose response experiment showed increases in collagenase mRNA up to 4000 U/ml of interferon-alpha-2b, but maximal increases in tissue inhibitor of metalloproteinase mRNA expression and maximal decrease in mRNA for type I procollagen at 2000 U/ml. For subsequent experiments cells were treated with either interferon-alpha-2b (2000 U/ml) or -gamma (1000 U/ml) for 96 hours. Quantitative analysis showed increases in tissue inhibitor of metalloproteinase-1 and collagenase mRNA (81% and 54%, respectively) in interferon-alpha-2b-treated hypertrophic scar fibroblasts. Under the same experimental conditions, interferon-alpha-2b had similar effects on normal dermal fibroblasts; however, interferon-gamma had a differential effect on the expression of mRNA for collagenase and tissue inhibitor of metalloproteinase-1. Cells treated with interferon-gamma showed increases in tissue inhibitor of metalloproteinase-1 mRNA (78% in hypertrophic scar and 56% in normal dermal fibroblasts) but decreases (59% and 42%, respectively) in collagenase mRNA. These effects appear to be selective because rehybridization of blots with a complementary DNA for tissue inhibitor of metalloproteinase-2 mRNA showed no marked alteration in the abundance of this transcript. Significantly greater collagenase activity was found in conditioned medium from interferon-alpha-2b-treated hypertrophic scar cells compared with that from interferon-gamma-treated cells. These findings suggest that interferon alpha-2b would have some advantages over interferon-gamma for the treatment of dermal fibroproliferative disorders, such as postburn hypertrophic scar.
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PMID:Interferons gamma and alpha-2b differentially regulate the expression of collagenase and tissue inhibitor of metalloproteinase-1 messenger RNA in human hypertrophic and normal dermal fibroblasts. 1717 46

Vocal fold scarring remains a therapeutic challenge. Our research group has indicated that bone marrow-derived stromal cells (BSCs) may have therapeutic potential in restoration of injured vocal folds. However, it is still unclear how BSCs restore the viscoelasticity of vocal fold mucosa. Since a feature of vocal fold scarring is the disorganization of the extracellular matrix (ECM), it is important to understand how BSCs produce ECM. The present study aimed to clarify ECM gene expression in BSCs, and also examined the effects of hepatocyte growth factor (HGF) on this expression. BSCs obtained from the femurs of four Sprague-Dawley rats were cultured with or without HGF. The mRNA expression of ECM components (type I procollagen, decorin, Has2, CD44, MMP-1, and GAPDH) were examined in cultured BSCs and the vocal fold mucosa by the reverse transcription-polymerase chain reaction (RT-PCR). The mRNA expression of Has2 and MMP-1 was significantly stronger in BSCs than in the vocal folds (P < 0.05). Expression of Has2 in BSCs was significantly increased by the administration of HGF (P < 0.05). There was no significant difference in the gene expression of other ECM molecules between BSCs and vocal fold mucosa. Increased expression of Has2 and MMP-1 genes from BSCs may have a positive potential in the treatment of vocal fold scarring.
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PMID:Expression of extracellular matrix proteins in the vocal folds and bone marrow derived stromal cells of rats. 1798 88

Matrix metalloproteinases (MMPs) induction and type I procollagen reduction in photoaging of the skin due to exposure to ultraviolet (UV) irradiation. Therefore, regulation of these genes has been suggested to be a useful tool to abolish skin aging. In this study, antioxidative plant ingredients used in traditional Chinese medicine, berberine (BBR) was investigated for their capacity to regulate MMP-1 and type I procollagen expression in human dermal fibroblasts. Our results showed that both basal and UV-induced MMP-1 expression was decreased by BBR. On the other hand, type I procollagen expression was dose-dependently increased by it. In addition, UV-induced reduction of type I procollagen expression is recovered by it. Therefore, we suggest that BBR may be a possible candidate for anti-skin aging agent.
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PMID:Berberine prevents UV-induced MMP-1 and reduction of type I procollagen expression in human dermal fibroblasts. 1816 89

We recently identified a missense single nucleotide polymorphism (SNP) in DDX5 (rs1140409, p.S480A) that enhances the risk of developing cirrhosis. DDX5 is an ATP-dependent RNA helicase and transcriptional modulator. We hypothesized that the activity of DDX5 in regulating fibrogenic gene transcription in hepatic stellate cells (HSCs) is altered by the S480A SNP. To test this, we employed two approaches: 1) transient overexpression of DDX5 cDNA or siRNA knockdown of endogenous DDX5, with replacement by either DDX5 wild type (WT) or SNP cDNA, or 2) stable expression of exogenous DDX5 WT and SNP in HSC lines. WT DDX5 mRNA in HSCs was inversely correlated with gene expression for alpha2(I) collagen, tissue inhibitor of metalloproteinase-1, and transforming growth factor-beta1. Stable DDX5 SNP-expressing cells had higher basal and transforming growth factor-beta1-stimulated expression and enhanced promoter activities of fibrogenic genes. DDX5 variant-expressing cells also had higher Smad3 and AP-1-responsive reporter activities. In a one-hybrid GAL4 system, co-expression of the DDX5 SNP variant with chimeras of GAL4 DNA binding domain linked to JunD or Sp1 displayed higher transactivation of a GAL4-responsive reporter than that of DDX5 WT. Increased fibrogenic gene expression in DDX5 SNP-expressing cells was associated with reduced recruitment of DDX5 homodimers to responsive promoters, but there was no difference in the recruitment of the co-repressor HDAC1 (histone deacetylase 1). These data suggest that DDX5 is a repressor of fibrogenic genes in HSCs through interaction with transcriptional complexes. The enhanced fibrogenic activity of the DDX5 risk variant is linked to a reduced repressive function toward these target genes.
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PMID:A DDX5 S480A polymorphism is associated with increased transcription of fibrogenic genes in hepatic stellate cells. 2002 62


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