Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.24 (mitogen-activated protein kinase)
95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Osteoclasts, the multinucleated giant cells that resorb bone, develop from monocyte-macrophage lineage cells. Osteoblasts or bone marrow stromal cells have been suggested to be involved in osteoclastic bone resorption. The recent discovery of new members of the tumor necrosis factor (TNF) receptor-ligand family has elucidated the precise mechanism by which osteoblasts/stromal cells regulate osteoclast differentiation and function. Osteoblasts/stromal cells express a new member of the TNF-ligand family "osteoclast differentiation factor(ODF)/osteoprotegerin ligand (OPGL)/TNF-related activation-induced cytokine (TRANCE)/receptor activator of NF-kB ligand (RANKL)" as a membrane associated factor. Osteoclast precursors which possess RANK, a TNF receptor family member, recognize ODF/OPGL/TRANCE/RANKL through cell-to-cell interaction with osteoblasts/stromal cells, and differentiate into osteoclasts in the presence of macrophage colony-stimulating factor. Mature osteoclasts also express RANK, and their bone-resorbingactivity is also induced by ODF/OPGL/TRANCE/RANKL which osteoblasts/stromal cells possess. Osteoprotegerin (OPG)/osteoclastogenesis inhibitory factor (OCIF)/TNF receptor-like molecule 1 (TR1) is a soluble decoy receptor for ODF/OPGL/TRANCE/RANKL. Activation of NF-kB and c-Jun N-terminal kinase through the RANK-mediated signaling system appears to be involved in differentiation and activation of osteoclasts.
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PMID:A new member of tumor necrosis factor ligand family, ODF/OPGL/TRANCE/RANKL, regulates osteoclast differentiation and function. 1008 Sep 18

Osteoprotegerin (OPG) and osteoclast differentiation factor (ODF) are crucial regulators of osteoclastogenesis. To determine the biological role of interleukin (IL)-18 produced by stromal/osteoblastic cells in osteoclastogenesis, we examined the effects of IL-18 on the OPG and ODF mRNA levels in these cells. When bone marrow stromal ST2 cells, osteoblastic MC3T3-E1 cells, and mouse calvarial osteoblasts were stimulated with IL-18, the expression of OPG mRNA, but not ODF mRNA, was transiently increased, its expression reaching a maximal level at 3 h after the beginning of the culture. In accordance with this observation, all these cells expressed the mRNAs of two IL-18 receptor components and MyD88, an adapter molecule involved in IL-18 signaling. Moreover, in these cells, mitogen-activated protein kinase was phosphorylated after stimulation with IL-18. These results suggest that stromal/osteoblastic cells are IL-18-responsive cells and that IL-18 may inhibit osteoclastogenesis by up-regulating OPG expression, without stimulation of ODF production, in stromal/osteoblastic cells.
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PMID:Interleukin-18 up-regulates osteoprotegerin expression in stromal/osteoblastic cells. 1118 Oct 55

Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is a member of the tumor necrosis factor family that is implicated in apoptosis, proliferation, migration, and inflammation. We describe our findings showing that TWEAK mediated the differentiation of RAW264.7 (RAW) monocyte/macrophage cells into multinuclear, functional osteoclasts. The effect of TWEAK was direct and not mediated by the receptor activator of nuclear factor-kappa B (NF-kappa B) ligand (RANKL) as shown by the use of TWEAK- or RANKL-neutralizing antibodies and by osteoprotegerin, a decoy receptor for RANKL. Recently, fibroblast growth factor-inducible 14 (Fn14) was suggested to be a receptor for TWEAK. We show that the Fn14/TWEAK receptor (TweakR) was not responsible for the osteoclastic effect of TWEAK on RAW cells. Flow cytometry analysis did not reveal the expression of Fn14/TweakR on RAW cells. Moreover, Fn14/TweakR-neutralizing antibodies did not block TWEAK-induced RAW cell differentiation into osteoclasts. This indicated that a second TweakR, TweakR2, exists on RAW cells and is responsible for mediating TWEAK-induced differentiation. We next compared the signaling pathways that are activated by the two receptors. TWEAK binding to TweakR2 activated the NF-kappa B, mitogen-activated protein kinase and c-Jun N-terminal kinase signaling cascades in RAW cells. In contrast, TWEAK binding to Fn14/TweakR activated the NF-kappa B and c-Jun N-terminal kinase pathways but induced only a weak activation of MAPK in HT-29 human colon adenocarcinoma cells expressing endogenous Fn14/TweakR. We propose that the biological effects of TWEAK are mediated by binding to one of at least two distinct receptors that induce differential activation of downstream signaling pathways.
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PMID:TWEAK mediates signal transduction and differentiation of RAW264.7 cells in the absence of Fn14/TweakR. Evidence for a second TWEAK receptor. 1279 80

Osteoprotegerin (OPG)/osteoclastogenesis inhibitory factor is a recently identified cytokine that belongs to the tumour necrosis factor receptor superfamily and regulates bone mass by inhibiting osteoclastic bone resorption. This study found that bone morphogenetic protein (BMP)-4 markedly increased the level of soluble OPG in the mouse bone-marrow-derived stromal cell line, ST2. In contrast, BMP-4 showed no effect on OPG ligand production in ST2 cells under similar conditions. Using an in vitro immunocomplex kinase assay, BMP-4 was found to activate p38 mitogen-activated protein (MAP) kinase. Pre-treatment of ST2 cells with SB203580 (a specific inhibitor of p38MAP kinase) inhibited BMP-4-induced increase in OPG, although PD98059 (a specific inhibitor of classic MAP kinase cascade) showed no effect on OPG production. These results clearly suggest that activation of the p38MAP kinase pathway is necessary for BMP-4-induced OPG induction in ST2 cells.
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PMID:Involvement of p38MAP kinase in bone morphogenetic protein-4-induced osteoprotegerin in mouse bone-marrow-derived stromal cells. 1282 91

Osteoprotegerin (OPG) is a decoy receptor for receptor activator of nuclear factor kappaB ligand (RANKL), an inducer of osteoclastogenesis via its receptor RANK. We recently demonstrated that OPG also exerts a direct effect in osteoclasts by regulating protease expression. Herein, we showed that OPG-induced pro-matrix metalloproteinase-9 activity was abolished by ras/MAPK inhibitors in purified osteoclasts. OPG induced the phosphorylation of p38 and ERK1/2 in RAW264.7 cells. Only p38 activation was totally abolished by a blocking anti-RANKL antibody or an excess of RANKL. Surface plasmon resonance experiments revealed that RANK, RANKL and OPG are able to form a tertiary complex. These results suggested a potential formation of a tertiary complex RANK-RANKL-OPG on osteoclasts. Thus, OPG is not only a soluble decoy receptor for RANKL but must be also considered as a direct effector of osteoclast functions.
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PMID:Cellular activity and signaling induced by osteoprotegerin in osteoclasts: involvement of receptor activator of nuclear factor kappaB ligand and MAPK. 1474 39

Osteoprotegerin Ligand (OPGL) is a member of the tumor necrosis factor ligand superfamily and has been shown to be involved in interactions between T cells and dendritic cells. Its role in monocyte effector function, however, has not been defined. In the present study a role for OPGL in activating monocytes/macrophages has been characterized. OPGL was found to up-regulate receptor activator of NF-kappaB (RANK) receptor expression on monocytes, regulate their effector function by inducing cytokine and chemokine secretion, activate antigen presentation through up-regulation of co-stimulatory molecule expression, and promote survival. This activation is mediated through the MAPK pathway as evidenced by activation of p38 and p42/44 MAPK and up-regulation of BCL-XL protein levels. A physiological role for OPGL in monocyte activation and effector function was tested in a model of lipopolysaccharide-induced endotoxic shock. Administration of receptor activator of NF-kappaB (RANK)-Fc to block OPGL activity in vivo was able to protect mice from death induced by sepsis, indicating a hitherto undescribed role for OPGL in monocyte function and in mediating inflammatory response. This was further tested in an animal model of inflammation-mediated arthritis. Treatment with RANK-Fc significantly ameliorated disease development and attenuated bone destruction. Thus, our study strongly suggests that administration of receptor fusion proteins to specifically block OPGL activity in vivo may result in blocking development of monocyte/macrophage-mediated diseases.
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PMID:A novel in vivo role for osteoprotegerin ligand in activation of monocyte effector function and inflammatory response. 1514 35

Inflammatory bone diseases are characterized by the presence of pro-inflammatory cytokines that regulate bone turnover. Osteoprotegerin (OPG) is a soluble osteoblast-derived protein that influences bone resorption by inhibiting osteoclast differentiation and activation. In the present study, we demonstrate that interleukin-1beta and tumor necrosis factor alpha induce OPG mRNA production and OPG secretion by osteoblast-like MG-63 cells. Maximum induction of OPG secretion by either cytokine requires activation of the p38 mitogen activated protein kinase (MAPK) pathway but neither the p42/p44 (ERK) nor the c-Jun N-terminal MAPK pathways. Induction of OPG mRNA by either cytokine is also p38 MAPK dependent. Taken together, these data indicate that cytokine-induced OPG gene expression and protein secretion are differentially regulated by specific MAP kinase signal transduction pathways.
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PMID:Inflammatory cytokines activate p38 MAPK to induce osteoprotegerin synthesis by MG-63 cells. 1572 Dec 97

Periodontitis, an inflammatory disorder of the supporting tissue of teeth, is one of the most common infectious diseases in humans. Periodontal pathogens promote inflammatory cytokines such as interleukin-1 (IL-1) and prostaglandin E2 (PGE2), resulting in alveolar bone destruction. In the present study, we examined the cellular and molecular mechanisms of IL-1-induced osteoclastogenesis using a coculture system of human periodontal ligament (PDL) cells and mouse spleen cells. IL-1alpha induced tartrate-resistant acid phosphatase positive (TRAP+) cell formation in a dose-dependent manner. IL-1alpha up-regulated receptor activator of NF-kappaB ligand (RANKL) and down-regulated osteoprotegerin (OPG) mRNA expression in PDL cells. The addition of cell-permeable PKI, an inhibitor of the cAMP/PKA signaling pathway, to the cocultures 8 h after the IL-1alpha stimulation inhibited IL-1alpha-induced TRAP+ cell formation. IL-1alpha-induced TRAP+ cell formation was completely blocked by either NS398, a selective inhibitor of cyclooxygenase (COX)-2, or PD98059, a specific inhibitor of extracellular signal-regulated kinase (ERK). Pretreatment with NS398 and PD98059 also inhibited both the up-regulation of RANKL and the down-regulation of OPG expression by IL-1alpha in PDL cells. IL-1alpha activated ERK phosphorylation and PD98059 greatly inhibited both COX-2 mRNA expression and PGE(2) production induced by IL-1alpha in PDL cells. In contrast, NEMO binding domain (NBD) peptide, a specific inhibitor of NF-kappaB signaling, did not affect COX2, RANKL, or OPG mRNA expression induced by IL-1alpha. These results suggest that IL-1alpha stimulates osteoclast formation by increasing the expression level of RANKL versus OPG via ERK-dependent PGE2 production in PDL cells.
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PMID:IL-1-induced receptor activator of NF-kappa B ligand in human periodontal ligament cells involves ERK-dependent PGE2 production. 1578 Sep 52

Mechanical stress is thought to play an important role in bone remodeling. However, the correlation between mechanical stress and bone remodeling is poorly understood. In this context, using a model of cyclic tensile strain (CTS) toward human osteoblasts, synthesis of osteoprotegerin (OPG) and soluble receptor activator of nuclear factor-kappaB ligand (sRANKL), and the activation of mitogen-activated protein kinases (MAPKs) were examined. The application of 7%, 0.25-Hz CTS once a day for 4 h for 3 successive days simultaneously caused an increase of OPG synthesis and a decrease of sRANKL release and RANKL mRNA expression in osteoblasts. As for MAPKs activation in osteoblasts with the application of CTS, p38 MAPK was activated 10-20 min after the application of CTS, but extracellular signal-regulated kinase (ERK1/2) and c-Jun NH2-terminal kinase (JNK) were not activated by such application. Furthermore, when CTS was applied once a day for 4 h for 1, 2, or 3 successive days to osteoblasts, p38 MAPK activation was maintained during the 3-day period but ERK1/2 activation was downregulated from day to day, simultaneously. Then, when CTS was applied once a day for 4 h for 3 successive days to osteoblasts pretreated with the p38 MAPK inhibitor SB203580 for 1 h, OPG synthesis was dose-dependently suppressed and inhibition of sRANKL release and RANKL mRNA expression was abrogated. These results indicate that biological responses of OPG and sRANKL synthesis in osteoblasts to the application of CTS are regulated via the p38 MAPK pathway and suggest that CTS might modulate and regulate bone metabolism.
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PMID:Regulation of synthesis of osteoprotegerin and soluble receptor activator of nuclear factor-kappaB ligand in normal human osteoblasts via the p38 mitogen-activated protein kinase pathway by the application of cyclic tensile strain. 1613 87

Mechanical loading of bone generates fluid flow within the mineralized matrix that exerts fluid shear stress (FSS) on cells. We examined effects of FSS on receptor activator of nuclear factor kappa B ligand (RANKL), a critical factor for osteoclast formation. Primary murine osteoblasts were subjected to pulsatile FSS (5 Hz, 10 dynes/cm(2)) for 1 h and then returned to static culture for varying times (post-FSS). Protein levels were measured by Western analysis and mRNA by Northern analysis, RT-PCR and quantitative PCR. There were 20- to 40-fold increases in RANKL mRNA at 2-4 h post-FSS. RANKL protein was induced by 2 h post-FSS and remained elevated for at least 8 h. Effects were independent of cyclooxygenase-2 activity. Small increases (up to three-fold) in mRNA of the decoy receptor for RANKL, osteoprotegerin, were seen. Five min of FSS, followed by static culture, was as effective in stimulating RANKL mRNA as 4 h of continuous FSS. FSS induced cAMP activity, and H-89, a protein kinase A (PKA) inhibitor, blocked the FSS induction of RANKL. H-89 also inhibited the PKC pathway, but specific PKC inhibitors, GF109203X and Go6983, did not inhibit FSS-induced RANKL. FSS induced phosphorylation of ERK1/2, and PD98059, an inhibitor of the ERK pathway, inhibited the FSS induction of RANKL mRNA 60%-90%. Thus, brief exposure to FSS resulted in sustained induction of RANKL expression after stopping FSS, and this induction was dependent on PKA and ERK signaling pathways. Increased RANKL after mechanical loading may play a role in initiating bone remodeling.
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PMID:Fluid flow induces Rankl expression in primary murine calvarial osteoblasts. 1651 40


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