Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Activated NF-kappaB plays an important role in the expression of matrix metalloproteinase (MMP)-1 and MMP-13 in rheumatoid arthritis and osteoarthritis. The objective of this study was to determine the effects of the NF-kappaB inhibitor pyrrolidine dithiocarbamate (PDTC) on the expression of MMPs in IL-1beta-stimulated fibroblast-like synoviocytes (FLSs) of rheumatoid arthritis patients. FLSs were treated with IL-1beta (10 ng/ml) for 24 h in the presence or absence of PDTC. The level of MMP-1 and MMP-13 increased in response to PDTC in time- and dose-dependent manners in IL-1beta-stimulated FLSs; the expressions of IL-6 and vascular endothelial growth factor (VEGF) decreased in a PDTC concentration-dependent manner. However, PDTC-mediated repression of IL-6 and VEGF expression was not observed in TNF-alpha-stimulated rheumatoid arthritis FLSs. In contrast, other NF-kappaB inhibitors, such as fenofibrate, N-acetylcysteine and MG132, decreased MMP expression in IL-1beta-stimulated FLSs. The stimulatory effect of PDTC on MMP expression was not mimicked by specific inhibitors of the mitogen-activated protein kinase (MAPK) signaling pathway. Treatments with 100 muM PDTC did not inhibit the phosphorylation of p-ERK1/2, p-P38, and p-JNK, or the transnuclear migration of NF-kappaB through degradation of IkappaB-alpha in IL-1beta-stimulated FLSs. These results suggest that the increase of MMP expression may occur in a stimuli-specific manner or by an NF-kappaB independent mechanism. Therefore, therapeutic NF-kappaB inhibitors should be thoroughly studied before their clinical use in treating rheumatoid arthritis, as undesirable genes may be upregulated through unknown mechanisms, possibly resulting in worse symptoms.
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PMID:Pyrrolidine dithiocarbamate, a NF-kappaB inhibitor, upregulates MMP-1 and MMP-13 in IL-1beta-stimulated rheumatoid arthritis fibroblast-like synoviocytes. 1937 26

In a screening program aimed at discovering anti-osteoarthritis (OA) drugs, we identified an imidazo[5,1-c][1,4]thiazine derivative, ITZ-1, that suppressed both interleukin-1beta (IL-1beta)-induced proteoglycan and collagen release from bovine nasal cartilage in vitro and suppressed intra-articular infusion of IL-1beta-induced cartilage proteoglycan degradation in rat knee joints. ITZ-1 did not inhibit enzyme activities of various matrix metalloproteinases (MMPs), which have pivotal roles in cartilage degradation, while it selectively inhibited IL-1beta-induced production of MMP-13 in human articular chondrocytes (HAC). IL-1beta-induced MMP production has been shown to be mediated by extracellular signal-regulated protein kinase (ERK), p38 kinase, and c-Jun N-terminal kinase (JNK) of the mitogen-activated protein kinase (MAPK) family signal transduction molecules. An ERK-MAPK pathway inhibitor (U0126), but not a p38 kinase inhibitor (SB203580) or a JNK inhibitor (SP600125), also selectively inhibited IL-1beta-induced MMP-13 production in HAC. Furthermore, ITZ-1 selectively inhibited IL-1beta-induced ERK activation without affecting p38 kinase and JNK activation, which may account for its selective inhibition of MMP-13 production. Inhibition of nitric oxide (NO)-induced chondrocyte apoptosis has been another area of interest as a therapeutic strategy for OA, and ITZ-1 also suppressed NO-induced death in HAC. These results suggest that ITZ-1 is a promising lead compound for a disease modifying anti-OA drug program.
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PMID:The chondroprotective agent ITZ-1 inhibits interleukin-1beta-induced matrix metalloproteinase-13 production and suppresses nitric oxide-induced chondrocyte death. 1954 81

The lack of beta1 integrins on chondrocytes leads to severe chondrodysplasia associated with high mortality rate around birth. To assess the impact of beta1 integrin-mediated cell-matrix interactions on the function of adult knee joints, we conditionally deleted the beta1 integrin gene in early limb mesenchyme using the Prx1-cre transgene. Mutant mice developed short limbed dwarfism and had joint defects due to beta1 integrin deficiency in articular regions. The articular cartilage (AC) was structurally disorganized, accompanied by accelerated terminal differentiation, altered shape, and disrupted actin cytoskeleton of the chondrocytes. Defects in chondrocyte proliferation, cytokinesis, and survival resulted in hypocellularity. However, no significant differences in cartilage erosion, in the expression of matrix-degrading proteases, or in the exposure of aggrecan and collagen II cleavage neoepitopes were observed between control and mutant AC. We found no evidence for disturbed activation of MAPKs (ERK1/2, p38, and JNK) in vivo. Furthermore, fibronectin fragment-stimulated ERK activation and MMP-13 expression were indistinguishable in control and mutant femoral head explants. The mutant synovium was hyperplastic and frequently underwent chondrogenic differentiation. beta1-null synoviocytes showed increased proliferation and phospho-focal adhesion kinase expression. Taken together, deletion of beta1 integrins in the limb bud results in multiple abnormalities of the knee joints; however, it does not accelerate AC destruction, perturb cartilage metabolism, or influence intracellular MAPK signaling pathways.
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PMID:Beta1 integrin deficiency results in multiple abnormalities of the knee joint. 1958 17

The IGF-I receptor (IGF-IR) was identified as a tumor progression factor, but its role in invasion and metastasis has been the subject of some controversy. Previously we reported that in murine lung carcinoma M-27 cells, overexpression of IGF-IR increased the synthesis and activation of matrix metalloproteinase (MMP)-2 via Akt/phosphatidylinositol 3-kinase signaling. In contrast, we show here that in these and other cells, IGF-IR overexpression reduced the constitutive and phorbol 12-myristate 13-acetate (PMA)-inducible expression of three protein kinase C (PKC)-regulated metalloproteinases, MMP-3, MMP-9, and MMP-13, in cultured cells as well as in vivo in sc tumors. To elucidate the underlying mechanism, we analyzed the effect of IGF-IR on PKC expression and activity using wild-type and IGF-IR-overexpressing (M-27(IGFIR)) tumor cells. Our results show that overexpression and activation of IGF-IR reduced PKC-alpha expression, PKC activity, and downstream ERK1/2 signaling, and these effects were reversed in cells expressing kinase (Y(1131,1135,1136)F) or C-terminal (Y(1250/51)F) domain mutants of IGF-IR. This reduction was due to transcriptional down-regulation of PKC-alpha as evidenced by reduced PKC-alpha mRNA expression in a phosphatidylinositol 3-kinase-dependent manner and a blockade of PKC-alpha promoter activation as revealed by a reporter gene assay. Finally, reconstitution of PKC-alpha levels could restore MMP-9 expression levels in these cells. Collectively, these results show that IGF-IR can inhibit PKC-alpha gene transcription and thereby block the synthesis of PMA-regulated MMPs, suggesting that within the same cells, IGF-IR can act as both a positive and negative regulator of MMP expression and function.
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PMID:The IGF-I receptor can alter the matrix metalloproteinase repertoire of tumor cells through transcriptional regulation of PKC-{alpha}. 1985 90

This study examined the hypothesis that the control of NADPH oxidase-2 (Nox2)-mediated reactive oxygen species (ROS) regulates the expression of matrix metalloproteinases (MMPs) and the migration of macrophages. Lipopolysaccharide (LPS) stimulation of Raw264.7 cells and mice peritoneal macrophages increased the expression of MMP-9, 10, 12 and 13 mRNA, and also increased Raw264.7 cell migration. Treatment with an antioxidant (N-acetyl cysteine) or Nox inhibitors strongly inhibited the expression of MMPs by LPS and inhibited cell migration. LPS caused ROS production in macrophages and increased the mRNA expression of Nox isoforms Nox1 and Nox2 by 20-fold and two-fold, respectively. While Nox1 small interfering RNA (siRNA) did not inhibit LPS-mediated expression of MMPs, Nox2 siRNA inhibited the expressions of MMP-9, 10 and 12. Neither Nox1 nor Nox2 siRNA influenced the LPS-mediated expression of MMP-13. In addition, NAC or apocynin attenuated LPS-induced ROS production and MMP-9 expression. MMP-9 expression and cell migration were controlled by ERK1/2-ROS signaling. Collectively, these results suggest that LPS stimulates ROS production via ERK and induce various types of MMPs expression and cell migration.
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PMID:Role of NADPH oxidase-2 in lipopolysaccharide-induced matrix metalloproteinase expression and cell migration. 1993 67

Prostaglandin E2 (PGE2) is one of pro-inflammatory mediators. PGE2 maintains the homeostasis of many organs including articular cartilage, and a previous report showed that continuous inhibition of PGE2 accelerates the progression of osteoarthritis (OA). While PGE2 inhibits matrix metalloprotease (MMP) expression in several types of cells, little is known on direct effects of PGE2 on MMP expression in articular chondrocytes. The objective of this study was to investigate direct effects of PGE2 on IL-1beta-induced MMP-1 and MMP-13 expression and the intracellular signaling in articular chondrocytes. PGE2 showed inhibitory effects on IL-1beta-induced MMP-1 and MMP-13 expression demonstrated by immunoblotting both in OA and normal chondrocytes, which was further confirmed by enzyme-linked immunosorbent assay and immunohistochemistry of explant cultures of articular cartilages. An EP4 agonist, ONO-AE1-329, mimicked the inhibitory effect of PGE2, while an EP4 antagonist, ONO-AE3-208, blocked the effects. PGE2 suppressed the phosphorylation of JNK and ERK MAP kinases, but only knockdown of JNK by specific siRNA mimicked the effect of PGE2. PGE2 further inhibited the phosphorylation of MKK4 without suppression of MKK7 phosphorylation, and of c-JUN to decrease expression levels of MMP-1 and MMP-13. These results demonstrate that PGE2 inhibits IL-1beta-induced MMP-1 and MMP-13 productions via EP4 by suppressing MKK4-JNK MAP kinase-c-JUN pathway.
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PMID:PGE2 inhibits MMP expression by suppressing MKK4-JNK MAP kinase-c-JUN pathway via EP4 in human articular chondrocytes. 1999 10

Overexpression of ErbB2 has been frequently found in mammary carcinoma. We have previously shown that the aberrant activation of H-Ras induces human breast cell invasion and migration. The present study was aimed at investigating the effect of ErbB2 overexpression on H-Ras-induced breast cell invasion and to elucidate the underlying mechanisms. Herein, we show that overexpression of ErbB2 promotes invasive and migratory abilities of H-Ras-activated MCF10A human breast epithelial cells through upregulation of matrix metalloproteinase (MMP)-13 and urokinase-type plasminogen activator (uPA). We also demonstrate that the p38 MAPK is an important signaling molecule in the ErbB2-induced upregulation of MMP-13 and uPA and invasion/migration of H-Ras MCF10A cells overexpressing ErbB2. The present study elucidating the molecular mechanism underlying ErbB2-induced promotion of H-Ras MCF10A cell invasion may provide invaluable information for understanding breast cancer progression and establishing therapeutic interventions for breast cancer.
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PMID:ErbB2-enhanced invasiveness of H-Ras MCF10A breast cells requires MMP-13 and uPA upregulation via p38 MAPK signaling. 2004 86

In the present study, we investigated potential synergism between IL-6 and IL-1 for the production of matrix metalloproteinases (MMPs) by the synovial cell line SW982. Cells were cultured with different combinations of IL-6, soluble IL-6 receptor (sIL-6R) and IL-1beta for 24h and production of MMPs was then measured. IL-6+sIL-6R, but not IL-6 alone, induced MMP-13 and MMP-3 production. IL-1beta also induced production of MMPs. Of interest, addition of IL-6+sIL-6R together with IL-1beta synergistically increased MMP production. Next, we analyzed the mechanism responsible for the synergistic effects of IL-6+sIL-6R and IL-1beta in combination. IL-1beta-induced MMP production was significantly augmented in the presence of sIL-6R. IL-1beta as well as IL-6+sIL-6R induced IL-6 production. Moreover, IL-6+sIL-6R significantly augmented expression of IL-1RI, but not IL-1RII, in SW982 cells. Responsiveness to IL-1beta was much higher in IL-6+sIL-6R-pretreated cells than non-treated cells in terms of MMP production. Finally, IL-6+sIL-6R-induced IL-1RI expression was inhibited by a STAT pathway inhibitor, but not a MAPK pathway inhibitor. These results suggest that increased expression of IL-1RI stimulated by IL-6+sIL-6R and the increased production of IL-6 on exposure to IL-1beta and IL-6+sIL-6R are involved in the observed synergistic effect on the production of MMPs by SW982 cells.
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PMID:IL-6 and IL-1 synergistically enhanced the production of MMPs from synovial cells by up-regulating IL-6 production and IL-1 receptor I expression. 2040 7

The protein kinase C (PKC) signaling pathway is a major regulator of cellular functions and is implicated in pathologies involving extracellular matrix remodeling. Inflammatory joint disease is characterized by excessive extracellular matrix catabolism, and here we assess the role of PKC in the induction of the collagenases, matrix metalloproteinase (MMP)-1 and MMP-13, in human chondrocytes by the potent cytokine stimulus interleukin-1 (IL-1) in combination with oncostatin M (OSM). IL-1 + OSM-stimulated collagenolysis and gelatinase activity were ameliorated by pharmacological PKC inhibition in bovine cartilage, as was collagenase gene induction in human chondrocytes. Small interfering RNA-mediated silencing of PKC gene expression showed that both novel (nPKC delta, nPKC eta) and atypical (aPKC zeta, aPKC iota) isoforms were involved in collagenase induction by IL-1. However, MMP1 and MMP13 induction by IL-1 + OSM was inhibited only by aPKC silencing, suggesting that only atypical isoforms play a significant role in complex inflammatory milieus. Silencing of either aPKC led to diminished IL-1 + OSM-dependent extracellular signal-regulated kinase (ERK) and signal transducer and activator of transcription (STAT) 3 phosphorylation, and c-fos expression. STAT3 gene silencing or ERK pathway inhibition also resulted in loss of IL-1 + OSM-stimulated c-fos and collagenase expression. Silencing of c-fos and c-jun expression was sufficient to abrogate IL-1 + OSM-stimulated collagenase gene induction, and overexpression of both c-fos and c-jun was sufficient to drive transcription from the MMP1 promoter in the absence of a stimulus. Our data identify atypical PKC isozymes as STAT and ERK activators that mediate c-fos and collagenase expression during IL-1 + OSM synergy in human chondrocytes. aPKCs may constitute potential therapeutic targets for inflammatory joint diseases involving increased collagenase expression.
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PMID:Protein kinase C isoforms zeta and iota mediate collagenase expression and cartilage destruction via STAT3- and ERK-dependent c-fos induction. 2046 8

Protein-disulfide isomerase-associated 3 (Pdia3) is a multifunctional protein hypothesized to be a membrane receptor for 1,25(OH)(2)D(3). In intestinal epithelium and chondrocytes, 1,25(OH)(2)D(3) stimulates rapid membrane responses that are different from genomic effects via the vitamin D receptor (VDR). In this study, we show that 1,25(OH)(2)D(3) stimulates phospholipase A(2) (PLA(2))-dependent rapid release of prostaglandin E(2) (PGE(2)), activation of protein kinase C (PKC), and regulation of bone-related gene transcription and mineralization in osteoblast-like MC3T3-E1 cells (WT) via a mechanism involving Pdia3. Pdia3 was present in caveolae based on co-localization with lipid rafts and caveolin-1. In Pdia3-silenced (Sh-Pdia3) cells, 1,25(OH)(2)D(3) failed to stimulate PKC and PGE(2) responses; in Pdia3-overexpressing cells (Ov-Pdia3), responses to 1,25(OH)(2)D(3) were augmented. Downstream mediators of Pdia3, PLA(2)-activating protein (PLAA) and arachidonic acid, stimulated similar PKC activation in wild-type, Sh-Pdia3, and Ov-Pdia3 cells supporting the hypothesis that Pdia3 mediates the membrane action of 1,25(OH)(2)D(3). Treatment of MC3T3-E1 cells with 1,25(OH)(2)D(3) for 9 min stimulated rapid phosphorylation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) and increased expression of alkaline phosphatase, MMP-13, and osteopontin but decreased expression of osteocalcin, osteoprotegerin (mRNA and protein), and smad2. These effects were attenuated in Sh-Pdia3 cells. Sh-Pdia3 cells produced higher numbers of von Kossa-positive nodules and alizarin red-positive nodules compared with WT cells with or without 1,25(OH)(2)D(3) treatment whereas Ov-Pdia3 did not show any mineralization. Our data suggest Pdia3 is an important initiator of 1,25(OH)(2)D(3)-stimulated membrane signaling pathways, which have both genomic and non genomic effects during osteoblast maturation.
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PMID:Protein-disulfide isomerase-associated 3 (Pdia3) mediates the membrane response to 1,25-dihydroxyvitamin D3 in osteoblasts. 2084 86


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