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)

The pleiotropic cytokine interleukin 1 (IL-1) is considered to be the principal inducer of mediators of cartilage degradation in both, osteoarthritis (OA) and rheumatoid arthritis (RA). IL-1 activates numerous signaling pathways involved in cartilage destruction and dedifferentiation of chondrocytes. In this study, we analyzed expression and functional effects of IL-1 in human chondrocytes. We found an IL-1-induced reduction in the expression of the cartilage specific proteoglycan aggrecan as an indicator for the IL-1-mediated dedifferentiation of chondrocytes. To block the IL-1-induced signaling pathways specifically, we incubated human chondrocytes and cartilage explants with IL-1 in the presence of different signal transduction inhibitors and analyzed their effect on aggrecan mRNA expression and IL-6 secretion. IL-6 has been found to act synergistically in the IL-1-induced suppression of the proteoglycan synthesis in chondrocytes. Our results led to the identification of p38MAPK and/or PI3K/JNK as being crucial for IL-1-induced IL-6 secretion by chondrocytes. IL-1-induced down-regulation of aggrecan expression was found to be mediated by p38MAPK and/or ERK1/2. The identification and characterization of these signaling pathways will enable us to develop new modulation strategies for therapeutic use in inflammatory joint diseases.
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PMID:p38MAPK mediates IL-1-induced down-regulation of aggrecan gene expression in human chondrocytes. 1652 25

Cartilage loss in osteoarthritis is characterized by cartilage degradation and chondrocyte death. Cartilage degradation is induced by activation of matrix-metalloproteinases (MMPs) activity and degradation of glycosaminoglycan (GAG) and collagen. Also, chondrocyte death is induced by the apoptosis through the activation of MAP kinase and caspases activities. On the basis of this background, our study was designed to examine the cartilage protective and anti-apoptotic effect of Aralia cordata. Cartilage explants and Chondrocytes were cultured from rabbit knee joint cartilage and treated by 5 ng/ml IL-1alpha. Cartilage and chondroprotective effects of Aralia cordata were determined by measuring (1) GAG and collagen expression, (2) GAG and collagen degradation, (3) TIMP and MMPs expression, and (4) TIMP and MMPs activity. Anti-apoptotic effects of Aralia cordata were determined by measuring (1) JNK and p38 MAP kinase expression, (2) apoptotic cells by flow cytometry, and (3) caspase-3 activity. In cartilage explants and chondroctyes treated by IL-1alpha, Aralia cordata showed the decrease of GAG and collagen degradation, decrease of MMPs (MMP-1, -3, -13) activity, and increase of TIMP-1 activity in a dose-dependent manner. Aralia cordata also showed anti-apoptotic effect by inhibition of early and late apoptotic cells, sub-G1 phase cells, and caspase-3 activity through the downregulation of JNK and p38 MAP kinase signaling pathway. Aralia cordata inhibited the cartilage and chondrocyte destruction through the downregulation of MMPs activities and the inhibition of proteoglycan and collagen degradation. Also, Aralia cordata inhibited the chondrocyte apoptosis through the downregulation of JNK and p38 MAP kinase signal, and the inhibition of caspase-3 activity.
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PMID:Effect of Aralia cordata extracts on cartilage protection and apoptosis inhibition. 1681 82

Versican is a large chondroitin sulfate proteoglycan produced by several tumor cell types, including malignant melanoma, which exists as four different splice variants. The presence of versican in the extracellular matrix plays a role in tumor cell growth, adhesion and migration, which could be altered by altering the ratio between versican isoforms. We have previously shown that overexpression of the V3 isoform of versican in human melanoma cell lines markedly reduces cell growth in vitro and in vivo, since V3-overexpressing (LV3SN) cultured cells as well as primary tumors arising from these cells grow slower than their vector-only counterparts (LXSN). In the present work, we have extended these observations to demonstrate that the delayed cell growth is due to multiple events since differences in proliferative index as well as in apoptosis are observed in LV3SN cells and tumors compared to LXSN. For example, LV3SN melanoma cells exhibit delayed activation of MAPK in response to EGF, we have also characterized further the primary tumors originated in nude mice from V3-transduced melanoma cells to determine if other events affect the V3 tumor phenotype. For example, hyaluronan content of LV3SN tumors was higher than in LXSN tumors, whereas other related matrix components and vascularization were unaffected. Furthermore, lung metastasis in nude mice occurred only in animals carrying LV3SN tumors, indicating a dual role for this molecule, both as an inhibitor of tumor growth and a metastasis inductor.
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PMID:V3 versican isoform expression has a dual role in human melanoma tumor growth and metastasis. 1684 33

Fibroblast growth factor-2 (FGF2) is a member of a prominent growth factor family that drives proliferation in a wide variety of cell types, including osteoblasts. The binding and signal transduction triggered by these mitogens is dependent on glycosaminoglycan (GAG) sugars, particularly of the heparan sulfate (HS) class. These are secreted in proteoglycan (PG) complexes, some of which become FGF co-receptors. The syndecans, the transmembrane forms of HSPG of which there are four members, act as multifunctional receptors for a variety of ligands involved in cell-extracellular matrix (ECM) adhesion as well as growth factor binding. To understand the role of syndecans in developing osteoblasts, the effects of exogenous FGF2 on syndecan expression were examined using primary rat calvarial osteoblasts. All four syndecan mRNAs were expressed in the osteoblasts, although only syndecan-4 was upregulated by FGF2 treatment in a dose-dependent manner. This upregulation could be abrogated by pretreatment with the protein synthesis inhibitor cycloheximide, suggesting that the upregulation of syndecan-4 by FGF2 is not a primary response. Osteoblast proliferation and mineralization were enhanced by exogenous FGF2 treatment, but could be specifically diminished by anti-syndecan-4 antibody pretreatment. This treatment also blocked FGF2-induced extracellular signal-regulated kinase activation, but not the expression of the bone-specific transcription factor Runx2. These results demonstrate that mitogen-triggered syndecan-4 expression is an intrinsic part of the pathways subtending osteoblast proliferation and mineralization.
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PMID:Regulated expression of syndecan-4 in rat calvaria osteoblasts induced by fibroblast growth factor-2. 1692 69

Intervertebral disc degeneration occurs commonly and is linked to persistent back pain and the development of disc herniation. The mechanisms responsible for tissue catabolism have not yet been fully elucidated. Previously we characterized an in vitro model of TNFalpha-induced nucleus pulposus degeneration, which demonstrates decreased expression of matrix macromolecules, increased expression of matrix degrading enzymes, and the activation of aggrecanase-mediated proteoglycan degradation [Seguin, C.A., Pilliar, R.M., Roughley, P.J., and Kandel, R.A. 2005. Tumor necrosis factor-alpha modulates matrix production and catabolism in nucleus pulposus tissue. Spine 30: 1940-1948]. This study explores the intracellular pathways activated during TNFalpha-induced matrix degradation. We demonstrate that in nucleus pulposus cells, the p38 and JNK pathways regulate induction of MMP-1 and -3; p38, JNK, and NF-kappaB regulate the induction of MMP-13; and ERK regulates the up-regulation of MT1-MMP mRNA in response to TNFalpha. Induction of ADAMTS-4 and -5 mRNA occurred downstream of NF-kappaB activation. Depletion of tissue proteoglycans was mediated by ERK and NF-kappaB-dependent "aggrecanase" activity, suggesting MT1-MMP and ADAMTS-4 and -5 as effectors of TNFalpha-induced tissue catabolism.
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PMID:Differential regulation of matrix degrading enzymes in a TNFalpha-induced model of nucleus pulposus tissue degeneration. 1693 45

Excessive release of basic fibroblast growth factor (bFGF) during loading and/or injury of the cartilage matrix may contribute to the onset or progression of osteoarthritis. This pathological role may be related to the ability of bFGF to decrease proteoglycan synthesis and to antagonize the activity of anabolic growth factors in cartilage such as insulin-like growth factor-1 and bone morphogenetic protein 7 (BMP7 or OP-1). Matrix metalloproteinase-13 (MMP-13), a catabolic cartilage-degrading enzyme, is dramatically up-regulated by inflammatory cytokines or by fibronectin fragments in articular chondrocytes. In this study, we investigated MMP-13 production by bFGF using human articular chondrocytes. Endogenous concentration of bFGF in synovial fluids collected from arthritis patients and asymptomatic subjects showed a good linear correlation with the endogenous levels of MMP-13. bFGF stimulation of MMP-13 was mediated at the transcriptional level and, at least in part, by stimulation of interleukin-1 production. Also, our findings suggest that bFGF stimulation of MMP-13 required the activation of multiple MAPKs (ERK, p38, and JNK) by bFGF, and more importantly, bFGF activation of protein kinase C (PKC) delta played a key role in the MMP-13 stimulation. Indeed, PKCdelta is the only isoform associated with MMP-13 stimulation among the PKC isoforms tested. PKCdelta controls the bFGF response by regulating multiple MAPK pathways. Our results suggest that PKCdelta activation is a principal rate-limiting event in the bFGF-dependent stimulation of MMP-13 in human adult articular chondrocytes. We propose that deregulation of cross-talk between MAPK and PKCdelta signaling may contribute to the etiology of osteoarthritis in human patients.
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PMID:Basic fibroblast growth factor stimulates matrix metalloproteinase-13 via the molecular cross-talk between the mitogen-activated protein kinases and protein kinase Cdelta pathways in human adult articular chondrocytes. 1731 29

Decorin (DCN) is a member of the small leucine-rich proteoglycan gene family. Many studies indicated that DCN inhibited fibrosis and scar-formation by neutralization of TGF-P and interfering the binding of TGF-beta with its receptor, which induced ectopic deposition of extracellular matrix. Additionally, DCN can prevent the proliferation and metastasis of tumor cells by activating EGFR/MAPK/p21 signal pathway and inhibiting the cell proliferation pathway mediated by EGF-EGFR. It is suggested that the recombinant DCN had potential pharmaceutical potency in treatment of chronic fibrosis and neoplasm for its critical biological activities and low immunogenicity.
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PMID:[The action of decorin in anti-fibrosis and anti-cancer]. 1733 27

We characterized the expression and functional properties of the ADP-sensitive P2Y(1) and P2Y(12) nucleotide receptors in glioma C6 cells cultured in medium devoid of serum for up to 96 h. During this long-term serum starvation, cell morphology changed from fibroblast-like flat to round, the adhesion pattern changed, cell-cycle arrest was induced, extracellular signal-regulated kinase (ERK1/2) phosphorylation was reduced, Akt phosphorylation was enhanced, and expression of the P2Y(12) receptor relative to P2Y(1) was increased. These processes did not reflect differentiation into astrocytes or oligodendrocytes, as expression of glial fibrillary acidic protein and NG2 proteoglycan (standard markers of glial cell differentiation) was not increased during the serum deprivation. Transfer of the cells into fresh medium containing 10% fetal bovine serum reversed the changes. This demonstrates that serum starvation caused only temporary growth arrest of the glioma C6 cells, which were ready for rapid division as soon as the environment became more favorable. In cells starved for 72 and 96 h, expression of the P2Y(1) receptor was low, and the P2Y(12) receptor was the major player, responsible for ADP-evoked signal transduction. The P2Y(12) receptor activated ERK1/2 kinase phosphorylation (a known cell proliferation regulator) and stimulated Akt activity. These effects were reduced by AR-C69931MX, a specific antagonist of the P2Y(12) receptor. On the other hand, Akt phosphorylation increased in parallel with the low expression of the P2Y(1) receptor, indicating the inhibitory role of P2Y(1) in Akt pathway signaling. The shift in nucleotide receptor expression from P2Y(1) to P2Y(12) would appear to be a new and important self-regulating mechanism that promotes cell growth rather than differentiation and is a defense mechanism against effects of serum deprivation.
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PMID:Expression and functional characterization of P2Y1 and P2Y12 nucleotide receptors in long-term serum-deprived glioma C6 cells. 1735 84

We demonstrate that a proteoglycan decorin (DCN) up-regulates the vascular endothelial growth factor (VEGF) expression with activation of VEGF regulating transcription factors Sp1, hypoxia-inducible factor 1alpha (HIF1alpha), and signal transducer and activator of transcription 3 (Stat3) via epidermal growth factor receptor (EGFR), mitogen-activated protein kinase extracellular signal-regulated kinase 1/2 (ERK1/2), and protein kinase B (AKT) pathways in DCN transfected mouse cerebral endothelial (MCE) cells. Treatment with pharmacological inhibitors and small interfering RNAs reveal that induction and activation of Sp1, HIF1alpha, and Stat3 facilitate their nuclear localization and binding to their specific motifs of the VEGF promoter and induce VEGF expression via two independent pathways, DCN/EGFR/phosphoinositide-3 kinase/AKT and DCN/EGFR/ERK1/2, respectively, in DCN synthesizing MCE cells. The cell type specific glycosylation protects Sp1 and HIF1alpha from proteosome degradation and plays an important and novel role in the regulation of VEGF in DCN transfected MCE cells. Induction of gelatinases (matrix metalloproteinase 2 and 9), the serine protease tissue plasminogen activator and plasmin by DCN transfection in MCE cells leads to extracellular proteolysis and to release of matrix-bound VEGF and activation of angiogenesis. In this study, we demonstrate that two independent downstream signal pathways, DCN/EGFR/ERK1/2 and DCN/EGFR/phosphoinositide-3 kinase/AKT, mediate up-regulation and activation of transcription factors of VEGF such as HIF1alpha, Stat3, and Sp1 and increase VEGF transcription and angiogenesis in MCE cells.
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PMID:Ectopic decorin expression up-regulates VEGF expression in mouse cerebral endothelial cells via activation of the transcription factors Sp1, HIF1alpha, and Stat3. 1802 Dec 92

Analysis of disc gene expression implicated IL-1 in the development of intervertebral disc degeneration (IDD) in a rabbit stab model. The purpose of these studies is to determine the role of p38 Mitogen Activated Protein Kinase (p38 MAPK) signaling in nucleus pulposus cell response to IL-1, and to compare rabbit nucleus pulposus (rNP) cell responses to IL-1 activation with those in a stab model of disc degeneration. NP cells maintained in alginate bead culture were exposed to IL-1, with or without p38 MAPK inhibition. RNA was isolated for reverse transcription polymerase chain reaction (RT-PCR) analysis of gene expression, conditioned media analyzed for accumulation of nitric oxide (NO) and prostaglandin E-2 (PGE-2), and proteoglycan synthesis measured after 10 days. IL-1 upregulation of mRNA for cycloxygenase-2 (COX-2), matrix metalloproteinase-3 (MMP-3), IL-1, and IL-6, was blunted by p38 inhibition while downregulation of matrix proteins (collagen I, collagen II, aggrecan) and insulin-like-growth-factor I (IFG-1) was also reversed. mRNA for tissue inhibitor of matrixmetalloproteinase-1 (TIMP-1) was modestly increased by IL-1, while those for Transforming Growth Factor-beta (TGF-beta) SOX-9, and versican remained unchanged. Blocking p38 MAPK reduced IL-1 induced NO and PGE-2 accumulation and partially restored proteoglycan synthesis. p38 MAPK inhibition in control cells increased mRNA for matrix proteins (aggrecan, collagen II, versican, collagen I) and anabolic factors (IGF-1, TGF, and SOX-9) from 50% to 120%, decreased basal PGE-2 accumulation, but had no effect on message for TIMP-1, MMP-3, or COX-2. Inhibition of p38 MAPK in cytokine-activated disc cells blunts gene expression and production of factors associated with inflammation, pain, and disc matrix catabolism while reversing IL-1 downregulation of matrix protein gene expression and proteoglycan synthesis. The results support the hypothesis that IL-1 could be responsible for many of the mRNA changes seen in rabbit NP in the stab model of disc degeneration, and uphold the concept that development of molecular techniques to block p38 MAPK could provide a therapeutic approach to slow the course of intervertebral disc degeneration.
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PMID:p38 MAPK inhibition modulates rabbit nucleus pulposus cell response to IL-1. 1830 37


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