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)

Tryptase has been suggested to take part in the pathophysiology of psoriasis mainly through the production of C3a by cleaving C3. However, studies using tryptase preparations of high purity do not support this notion. Therefore, although tryptase is unanimously believed to be involved in the immunopathogenesis of psoriasis, no convincing mechanism has been proposed for its role. This paper proposes several mechanisms by which this enyme may exert its role in the pathobiology of psoriasis. Tryptase is a mitogen for epithelial cells and stimulates IL-8 production and ICAM-1 expression by these cells. It also induces the expression of mRNA for IL-1beta and IL-8 and stimulates the selective release of IL-8 from endothelial cells and TNF-alpha, IL-1beta, and IL-6 from lymphocytes and monocytes. Besides itself being a chemoattractant for neutrophils, tryptase activates mast cells and generates kinins from kininogen, thereby playing a crucial role in leukocyte infiltration into psoriatic lesions. This enzyme also induces leukocyte infiltration partly through activating endothelial PAR-2, which contributes to leukocyte rolling, adherence and recruitment by inducing the release of endothelial platelet-activating factor. Through activating PAR-2, tryptase could also trigger the development of Langerhans cells which play a crucial role in the pathophysiology of psoriasis. This enzyme is a mitogen for fibroblasts, which are probably involved in the pathophysiology of psoriasis through production of insulin-like growth factor-I (IGF-I). Tryptase is a gelatinase and also activates stromelysin-1 (MMP-3), thereby contributing to the disruption of psoriatic basement membrane and to the joint damage seen in psoriatic arthritis. Increase of tryptase levels following trauma could also provide a mechanism for Koebner phenomenon seen in psoriasis.
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PMID:Possible molecular mechanisms to account for the involvement of tryptase in the pathogenesis of psoriasis. 1627 51

Catabolic cytokine and anabolic growth factor pathways control destruction and repair in osteoarthritis (OA). A unidirectional TNF-alpha/IL-1-driven cytokine cascade disturbs the homeostasis of the extracellular matrix of articular cartilage in OA. Although chondrocytes in OA cartilage overexpress anabolic insulin-like growth factor (IGF) and its specific receptor (IGFRI) autocrine TNF-alpha released by apoptotic articular cartilage cells sets off an auto/paracrine IL-1-driven cascade that overrules the growth factor activities that sustain repair in degenerative joint disease. Chondroprotection with reappearance of a joint space that had disappeared has been documented unmistakably in peripheral joints of patients suffering from spondyloarthropathy when treated with TNF-alpha-blocking agents that repressed the unidirectional TNF-alpha/IL-1-driven cytokine cascade. A series of connective tissue structure-modifying agents (CTSMAs) that directly affect IL-1 synthesis and release in vitro and down-modulate downstream IL-1 features, e.g. collagenase, proteoglycanase and matrix metalloproteinase activities, the expression of inducible nitric oxide synthase, the increased release of nitric oxide, and the secretion of prostaglandin E(2), IL-6 and IL-8, have been shown to possess disease-modifying OA drug (DMOAD) activities in experimental models of OA and in human subjects with finger joint and knee OA. Examples are corticosteroids, some sulphated polysaccharides, chemically modified tetracyclines, diacetylrhein/rhein, glucosamine and avocado/soybean unsaponifiables.
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PMID:Chondroprotective drugs in degenerative joint diseases. 1627 82

We studied the biochemical characteristics of human knees with deficient anterior cruciate ligaments (ACL) and analysed their relationship to the time after ligamentous injury. Thirty-two patients with isolated ACL-injured knees and six healthy volunteers were enrolled. Synovial fluid samples were centrifuged after aspiration during arthroscopic examination, and aliquots of supernatant were frozen and stored at -80 degrees C. The samples were analysed for interleukin (IL)-1beta, tumour necrosis factor (TNF)-alpha, IL-6, matrix metalloproteinase (MMP)-3, and tissue inhibitor of metalloproteinase (TIMP)-1 using commercially available sandwich enzyme-linked immunosorbent assay. In fluid from ACL-injured knees, the average concentrations of IL-6, MMP-3 and TIMP-1 were highly elevated in comparison with normal controls. There was a statistically significant correlation between the concentrations of MMP-3 and IL-6. The IL-6 and TIMP-1 concentrations were interrelated. The concentration of MMP-3 remained high, independent of the duration since the injury, whereas the TIMP-1 and IL-6 levels decreased. The results suggest that the timing of the treatment of an ACL-injured knee might be of importance.
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PMID:Changes in biochemical parameters after anterior cruciate ligament injury. 1633 57

TNFalpha and IL-1 are the pivotal cytokines involved in rheumatoid arthritis (RA). More recently, the biological therapy targeting TNFalpha or IL-1 has been impressively effective for many RA patients, however, it remains insufficient in some patients. In the present study, we examined the combined effects of two agents against TNFalpha and IL-1 in human RA synovial membrane. Synovial explants (an ex vivo model) and synovial fibroblasts (an in vitro model) were prepared from 11 RA patients, and then anti-TNFalpha antibody (Anti-TNFalpha) and IL-1 receptor antagonist (IL-1Ra), either alone or in combination, were added to the synovial explants and fibroblasts. IL-6 and MMP-3 production were measured after incubation. As a result, their production significantly decreased by the combination of agents compared with the control group in both the synovial explants and fibroblasts. The efficacy of this combination was also observed for IL-6 production compared with each agent alone in the synovial explants, and for IL-6 and MMP-3 production compared with each agent alone in the synovial fibroblasts. Therefore, the combination of Anti-TNFalpha and IL-1Ra appears more beneficial in synovial membrane, particularly when compared with a single agent alone.
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PMID:The combined effects of anti-TNFalpha antibody and IL-1 receptor antagonist in human rheumatoid arthritis synovial membrane. 1640 55

Increased inflammatory activity is known to accompany aging. Single nucleotide polymorphisms of inflammatory mediator genes might therefore affect the aging process. Relation of eight SNPs (tumor necrosis factor-alpha [TNF-alpha] -1031 T/C, interleukin-10 [IL-10] -819 T/C, IL-1beta -511 C/T, IL-6 -634 C/G, IL-18 -607 A/C, transforming growth factor-beta [TGF-beta] +869 C/T, matrix metalloproteinase-1 [MMP-1] -1607 1G/2G, and MMP-3 -1171 5A/6A) with age or gender was evaluated in 500 Japanese persons (mean age: 56.7 years old, range: 19-100) by the chi-square test. There was a significant association of IL-10 -819 T/C with age (p =.0026). The association remained significant after multivariate logistic regression analysis (odds ratio for an age interval for 1 year, 1.009; 95% CI, 1.002-1.016). Furthermore, the genotype distribution of IL-10 -819 T/C was completely consistent with that of -592 A/C. These data suggest that IL-10 -819 T/C and -592 A/C may be a promising candidate for an aging-related gene in a Japanese population.
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PMID:Association of interleukin-10 promoter single nucleotide polymorphisms -819 T/C and -592 A/C with aging. 1642 84

An imbalance in the matrix metalloproteinase (MMP) : tissue inhibitor of MMP (TIMP) ratio may be associated with tissue injury. Here, we studied the regulation of TIMP and MMP gene expression in primary glial cultures to ascertain the factors involved in the regulation of these genes in conditions of inflammatory neuropathology. Astrocytes were found to basally express TIMP-1 and TIMP-3 mRNA while microglia expressed only TIMP-2 mRNA. TIMP-4 mRNA was not detectable in either cell type. Treatment with interferon-alpha (IFN-alpha), IFN-gamma, interleukin-3 (IL-3), IL-6 or tumor necrosis factor-alpha (TNF-alpha) did not alter expression of the TIMP genes. However, in astrocytes, but not in microglia, serum, IL-1beta or lipopolysaccharide (LPS) evoked a dose- and time-dependent increase in TIMP-1 mRNA and a coincident down-regulation of the TIMP-3 gene. Astrocytes were found to express mRNA constitutively for MMPs -3, -11 and -14. In contrast, microglia expressed only MMP-12 mRNA under basal conditions. IL-1beta enhanced MMP-3 mRNA levels while LPS increased the MMP-3, -9, -12, -13 and -14 mRNAs. Our findings reveal that regulatory control of TIMP and MMP gene expression by glial cells is agonist- and cell-type specific, and suggest that innate immune signals govern the temporal and spatial expression patterns of TIMP and MMP genes in neuroinflammatory conditions of the CNS.
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PMID:Cell and agonist-specific regulation of genes for matrix metalloproteinases and their tissue inhibitors by primary glial cells. 1689 21

Dental pulp destruction is believed to be regulated, in part, by the matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs). Cytokines are believed to be important in the pathogenesis of pulpitis. This study examined the effects that TNF-alpha, IL-1beta, IL-6, and TGF-beta1 have on the collagen degradation mediated by pulp fibroblasts utilizing a cell-mediated collagen degradation assay. Reverse transcriptase-polymerase chain reaction, Western blot analyses, and zymography were utilized to examine multiple MMPs and TIMPs. The collagen degradation mediated by these cells was stimulated by these cytokines. TNF-alpha, IL-1beta, and IL-6 increased the mRNA and/or protein expression of MMP-1, MMP-2, and MMP-3. TGF-beta1 decreased MMP-1 mRNA expression, while only slightly affecting the MMP-2 and MMP-3 mRNA and/or protein. These cytokines did not affect the expression of TIMP-1 or TIMP-2. These results suggest that these cytokines affect pulp destruction, in part, by differentially regulating the MMPs and TIMPs.
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PMID:The effects of tumor necrosis factor-alpha, interleukin-1beta, interleukin-6, and transforming growth factor-beta1 on pulp fibroblast mediated collagen degradation. 1693 28

Helicobacter pylori cag pathogenicity island (PAI) is a major determinant of gastric injury via induction of several matrix metalloproteinases (MMPs). In the present study, we examined the influence of the cag PAI on gastric infection and MMP-9 production in mice and in cultured cells. A new mouse colonizing Indian H. pylori strain (AM1) that lacks the cag PAI was used to study the cag PAI importance in inflammation. Groups of C57BL/6 mice were inoculated separately with H. pylori strains AM1 and SS1 (cag+), gastric tissues were histologically examined, and bacterial colonization was scored by quantitative culture. Mice infected with either cag+ or cag- H. pylori strains showed gastric inflammation and elevated MMP-3 production. Significant up-regulation of pro-MMP-9 secretion and gene expression in H. pylori infected gastric tissues indicate dispensability of cag PAI for increased pro-MMP-9 secretion and synthesis in mice. In agreement, cell culture studies revealed that both AM1 and SS1 were equipotent in pro-MMP-9 induction in human gastric epithelial cells. Both strains showed moderate increase in MMP-2 activity in vivo and in vitro. In addition, increased secretion of tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, and IL-6 induced pro-MMP-9 secretion and synthesis in AM1 or SS1 strain-infected mice suggesting elicitation of pro-inflammatory cytokines by both cag- and cag+ genotype. Moreover, tissue inhibitors of metalloproteinase-1 expression were decreased with increase in pro-MMP-9 induction. These data show that H. pylori may act through different pathways other than cag PAI-mediated for gastric inflammation and contribute to up-regulation of MMP-9 via pro-inflammatory cytokines.
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PMID:Cag pathogenicity island-independent up-regulation of matrix metalloproteinases-9 and -2 secretion and expression in mice by Helicobacter pylori infection. 1696 23

Numerous investigations have reported the efficacy of exogenous hyaluronan (HA) in modulating acute and chronic inflammation. The current study was performed to determine the in vitro effects of lower and higher molecular weight HA on lipopolysaccharide (LPS)-challenged fibroblast-like synovial cells. Normal synovial fibroblasts were cultured in triplicate to one of four groups: group 1, unchallenged; group 2, LPS-challenged (20 ng/ml); group 3, LPS-challenged following preteatment and sustained treatment with lower molecular weight HA; and group 4, LPS-challenged following pretreatment and sustained treatment with higher molecular weight HA. The response to LPS challenge and the influence of HA were compared among the four groups using cellular morphology scoring, cell number, cell viability, prostaglandin E2 (PGE2) production, IL-6 production, matrix metalloproteinase 3 (MMP3) production, and gene expression microarray analysis. As expected, our results demonstrated that LPS challenge induced a loss of characteristic fibroblast-like synovial cell culture morphology (P < 0.05), decreased the cell number (P < 0.05), increased PGE2 production 1,000-fold (P < 0.05), increased IL-6 production 15-fold (P < 0.05), increased MMP3 production threefold (P < 0.05), and generated a profile of gene expression changes typical of LPS (P < 0.005). Importantly, LPS exposure at this concentration did not alter the cell viability. Higher molecular weight HA decreased the morphologic change (P < 0.05) associated with LPS exposure. Both lower and higher molecular weight HA significantly altered a similar set of 21 probe sets (P < 0.005), which represented decreased expression of inflammatory genes (PGE2, IL-6) and catabolic genes (MMP3) and represented increased expression of anti-inflammatory and anabolic genes. The molecular weight of the HA product did not affect the cell number, the cell viability or the PGE2, IL-6, or MMP3 production. Taken together, the anti-inflammatory and anticatabolic gene expression profiles of fibroblast-like synovial cells treated with HA and subsequently challenged with LPS support the pharmacologic benefits of treatment with HA regardless of molecular weight. The higher molecular weight HA product provided a cellular protective effect not seen with the lower molecular weight HA product.
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PMID:Effects of hyaluronan treatment on lipopolysaccharide-challenged fibroblast-like synovial cells. 1721 81

The widespread distribution of Toll-like receptors (TLRs) and their ligands raises the question whether they contribute to the production of inflammatory and tissue destructive molecules in rheumatoid arthritis (RA). We examined the expression and function of TLR2 and TLR4 and their downstream signaling adaptors MyD88 and Mal/TIRAP in synovial membrane cultures from RA tissue. Both TLR2 and TLR4 were detected by flow cytometry, and stimulation with TLR2 and TLR4 ligands augmented the spontaneous production of tumor necrosis factor-alpha, interleukin (IL)-6, and IL-8, indicating that TLR2 and TLR4 are functional in these cultures. In addition, overexpression of dominant-negative forms of MyD88 and Mal/TIRAP significantly down-regulated the spontaneous production of cytokines tumor necrosis factor-alpha, IL-6, and vascular endothelial growth factor, and enzymes MMP-1, MMP-2, MMP-3, and MMP-13 in RA synovial membrane cell cultures. Because TLR2 and TLR4 require both MyD88 and Mal/TIRAP for signaling, this study suggests that TLR function may regulate the expression of these factors in the RA synovium. Conditioned media from synovial membrane cell cultures stimulated human macrophages in a MyD88- and Mal-dependent manner, suggesting the release of a TLR ligand(s) from these cells. Thus, TLRs not only protect against infection but may also promote the inflammatory and destructive process in RA.
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PMID:The Toll-like receptor adaptor proteins MyD88 and Mal/TIRAP contribute to the inflammatory and destructive processes in a human model of rheumatoid arthritis. 1725 20


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