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)

Transcription factors NFATc1, PU.1, and MITF collaborate to regulate specific genes in response to colony-stimulating factor-1 (CSF-1) and receptor activator of NF-kappaB ligand (RANKL) signaling during osteoclast differentiation. However, molecular details concerning timing and mechanism of specific events remain ill-defined. In bone marrow-derived precursors, CSF-1 alone promoted assembly of MITF-PU.1 complexes at osteoclast target gene promoters like cathepsin K and acid 5 phosphatase without increasing gene expression. The combination of RANKL and CSF-1 concurrently increased the levels of MAPK-phosphorylated forms of MITF, p38 MAPK, and SWI/SNF chromatin-remodeling complexes bound to these target promoters and markedly increased expression of the genes. NFATc1 was subsequently recruited to complexes at the promoters during terminal stages of osteoclast differentiation. Genetic analysis of Mitf and Pu.1 in mouse models supported the critical interaction of these genes in osteoclast differentiation. The results define MITF and PU.1 as nuclear effectors that integrate CSF-1/RANKL signals during osteoclast differentiation to initiate expression of target genes, whereas a complex that includes NFATc1 may act to maintain target gene expression in differentiated cells.
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PMID:MITF and PU.1 recruit p38 MAPK and NFATc1 to target genes during osteoclast differentiation. 1740 83

It has been reported that deer antler extract has anti-bone resorptive activity in vivo. However, little is known about the cellular and molecular mechanism of this effect. In this study, we investigated the effects of deer antler extracts on osteoclast differentiation and bone-resorption in vitro. Chloroform extract (CE-C) of deer antler inhibited osteoclast differentiation in mouse bone marrow cultures stimulated by receptor activator of NF-kappaB ligand (RANKL) and macrophage-colony stimulating factor (M-CSF). CE-C suppressed the activation of extracellular signal-regulated kinase (ERK), protein kinase B (PKB/Akt) and inhibitor of kappa B (I-kappaB) by RANKL in osteoclast precursor cells. It also inhibited the bone resorptive activity of differentiated osteoclasts that was accompanied by disruption of actin rings and induction of the apoptosis. These results demonstrate deer antler extract may be a useful remedy for the treatment of bone-resorption diseases such as osteoporosis.
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PMID:Chloroform extract of deer antler inhibits osteoclast differentiation and bone resorption. 1764 68

In this work, we investigated the effect of inorganic phosphate (Pi) on the differentiation of monocyte/macrophage precursors into an "osteoclastic" phenotype, and we delineated the molecular mechanisms which could be involved in this phenomenon. This was achieved by stimulating human peripheral blood monocytic cells and RAW 264.7 monocyte-macrophage precursor cells to differentiate into osteoclast-like cells in the presence of receptor activator of NF-kappaB ligand (RANKL) and macrophage colony-stimulating factor (M-CSF). RANKL has been previously reported to stimulate the signaling kinases ERK 1/2, p38, Akt, JNK, and the DNA-binding activity of the transcription factors AP-1 and NF-kappaB. Increase in extracellular Pi concentration (1.5-4.5 mM) dose-dependently inhibits both osteoclastic differentiation and bone resorption activity induced by RANKL and M-CSF. Pi was found to specifically inhibit the RANKL-induced JNK and Akt activation, while RANKL-induced p38 and ERK 1/2 phosphorylation were not significantly affected. Moreover, we found that Pi significantly reduced the RANKL-stimulated DNA-binding activity of NF-kappaB. The effects of Pi on osteoclast differentiation and DNA-binding activity of NF-kappaB were prevented by Foscarnet, a sodium-phosphate cotransport inhibitor, suggesting that the effects of Pi occur subsequently to its intake. These results demonstrate that Pi downregulates the differentiation of osteoclasts via a negative feedback exerted on RANK-RANKL signaling.
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PMID:High extracellular inorganic phosphate concentration inhibits RANK-RANKL signaling in osteoclast-like cells. 1789 87

Platelets induce osteoclastogenesis in total bone marrow cultures where hematopoietic cells can interact with stromal cells. Whether or not activated platelets directly act on hematopoietic cells to promote their differentiation into osteoclasts remains unknown. Here we report that platelet releasates (PRS) increase osteoclastogenesis in stroma-depleted, macrophage colony-stimulating factor (M-CSF)-dependent bone marrow cells when cultured in the presence of receptor activator of NF-kappaB ligand (RANKL). The increased number of tartrate-resistant acid phosphatase-positive multinucleated cells (MNC) was paralleled by an enhanced transcription of osteoclast specific genes. Osteoclastogenesis was observed with hematopoietic cells previously depleted of B-cells or T-cells. Immunoprecipitation of transforming growth factor-beta (TGF-beta) decreased the osteoclastogenic capacity of the PRS. PRS enhanced phosphorylation of Smad-2, a downstream signaling mediator of TGF-beta. PRS increased phosphorylation of p38 and c-Jun NH(2)-terminal kinase (JNK), whereas only blocking of p38 but not JNK signaling suppressed osteoclastogenesis. These results suggest that activated platelets can enhance osteoclastogenesis by providing a source of TGF-beta and by activating osteoclastogenic signaling pathways.
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PMID:Activated platelets positively regulate RANKL-mediated osteoclast differentiation. 1795 25

Osteoclastogenesis is induced by differentiation of hemopoietic cells of monocyte-macrophage lineage into bone-resorbing osteoclasts. The process is initiated by receptor activator of NF-kappaB ligand (RANKL) and resultant activation of mitogen-activated protein kinases (MAPK), including extracellular signal-regulated kinase (ERK)1/2, as well as the NFkappaB pathway. Phenethyl isothiocyanate (PEITC), a phytochemical present in various cruciferous plants, has been shown to disrupt those signaling pathways in several cell types. In this study, we examined the efficacy of PEITC for suppressing RANKL-induced osteoclastogenesis in RAW264.7 murine macrophages and addressed the underlying molecular mechanisms. PEITC (2-10 microM) suppressed osteoclastogenesis in a concentration dependent manner, as detected by tartarate-resistant acid phosphatase (TRAP) activity and microscopic observations. RANKL-up-regulated extracellular signal-regulated kinase (ERK)1/2 and p38 mitogen-activated protein kinase (MAPK) activities were attenuated by PEITC, whereas c-Jun N-terminal kinase (JNK1/2) activation was increased. PEITC also abrogated the RANKL-induced degradation of IkappaB-alpha, a suppressive partner of nuclear factor kappaB (NFkappaB), thereby inhibiting transcription activity, as detected by a reporter assay. In addition, PEITC reduced the level of NFkappaB-dependent mRNA expression of nuclear factor of activated T cell (NFAT)c1, a master regulator of osteoclastogenesis. Our results indicate that PEITC is a promising agent for treatment of osteoclastogenesis with a reasonable action mechanism.
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PMID:Phenethyl isothiocyanate suppresses receptor activator of NF-kappaB ligand (RANKL)-induced osteoclastogenesis by blocking activation of ERK1/2 and p38 MAPK in RAW264.7 macrophages. 1819 96

Interleukin-6 (IL-6) is a multifunctional cytokine produced by various cells to regulate hematopoiesis, inflammation, immune responses, and bone homeostasis. IL-6 is also known to modulate the differentiation of osteoblasts and osteoclasts. IL-6 is believed to play a positive regulatory role in osteoclast differentiation by inducing the expression of receptor activator of NF-kappaB ligand (RANKL) on the surface of osteoblasts: RANKL then interacts with RANK expressed on osteoclast progenitors, inducing osteoclast differentiation via the RANK signaling pathway, which involves NF-kappaB, JNK, and p38. In this report, we demonstrate that IL-6 can also directly act on osteoclast progenitors to suppress their differentiation via an inhibition of RANK signaling pathways. IL-6 specifically suppressed RANK-mediated IkappaB degradation and JNK activation. Microarray analysis revealed that costimulation with IL-6 and RANKL up-regulates the transcription of MKP1 and MKP7, which encode enzymes that dephosphorylate JNK, and down-regulates the transcription of Senp2 and Cul4A, which are related to the ubiquitin pathway. Thus, IL-6 directly acts on osteoclast progenitors and suppresses their differentiation by regulating the transcription of specific genes related to MAPK phosphatases and the ubiquitin pathway.
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PMID:Interleukin-6 directly inhibits osteoclast differentiation by suppressing receptor activator of NF-kappaB signaling pathways. 1829 9

The 4-1BB is a costimulatory molecule similar to the receptor activator of NF-kappaB ligand (RANKL), both of which are key factors for the differentiation of osteoclasts and are expressed mainly by activated T cells. The 4-1BB shares common signaling pathways with RANK, suggesting a potential role in osteoclastogenesis. In this study, the role of 4-1BB and 4-1BB ligand (4-1BBL) in osteoclastogenesis was investigated using 4-1BB(-/-) and 4-1BB(+/+) mice. Osteoclast precursors normally express 4-1BB and 4-1BBL after exposure to RANKL, which was confirmed by semi-quantitative RT-PCR and flow cytometry. The 4-1BB(-/- )mice had a slightly increased bone mass accompanied by a reduced osteoclastogenic ability of 4-1BB(-/-) bone marrow-derived macrophages (BMM) ex vivo. In addition, 4-1BB(-/-) BMM demonstrated hypophosphorylation of JNK and p38 and decreased induction of c-Fos in response to RANKL stimulation. Retroviral transduction of wild-type as well as partial-length 4-1BB, which lacks TNF receptor-associated factor 2-binding sites for signaling, restored the osteoclastogenic ability of 4-1BB(-/-) BMM. Furthermore, both recombinant 4-1BB and 4-1BBL enhanced RANKL-induced osteoclastogenesis by 4-1BB(+/+) BMM and the induction of c-Fos and NFATc1.Together, these results indicate that 4-1BBL and 4-1BB expressed on osteoclast precursors enhance RANKL-induced osteoclastogenesis via bi-directional signaling, findings that may delineate the complex nature of the 4-1BBL and 4-1BB interaction.
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PMID:The 4-1BB ligand and 4-1BB expressed on osteoclast precursors enhance RANKL-induced osteoclastogenesis via bi-directional signaling. 1842 90

Numerous studies have indicated that inflammatory cytokines play a major role in osteoclastogenesis, leading to the bone resorption that is frequently associated with osteoporosis. Paeonol (2'-hydroxy-4'-methoxyacetophenone), the main active compound of the traditionally used Chinese herb Paeonia lactiflora Pallas, has anti-inflammatory activity. Here we found that paeonol markedly inhibited the receptor activator of nuclear factor kappa B ligand (RANKL) plus macrophage colony stimulating factor (M-CSF)-induced osteoclastic differentiation from bone marrow stromal cells and RAW264.7 macrophage cells. In addition, in an assay of osteoclast activity on substrate plates, paeonol significantly decreased the resorption activity of mature osteoclasts. Treatment of RAW264.7 macrophages with RANKL induced extracellular signal-regulated kinases (ERK), p38 and c-Jun N-terminal kinase (JNK) phosphorylation. However, RANKL-induced ERK, p38 but not JNK phosphorylation was attenuated by paeonol. Furthermore, RANKL-mediated increase of IkappaBalpha phosphorylation, p65 phosphorylation at Ser(536), kappaB-luciferase activity and NF-kappaB binding activity was inhibited by paeonol. In addition, paeonol also prevented the bone loss inducing by ovariectomy in vivo. Our data suggest that paeonol inhibits osteoclastogenesis from bone marrow stromal cells and macrophage cells via attenuated of RANKL-induced ERK, p38 and NF-kappaB activation, which in turn protect bone loss from ovariectomy.
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PMID:Paeonol inhibits RANKL-induced osteoclastogenesis by inhibiting ERK, p38 and NF-kappaB pathway. 1849 14

In bone remodeling, an imbalance caused by increased bone resorption over bone formation leads to adult skeletal diseases such as osteoporosis. Therefore, the development of anti-resorptive agents has still gained more interest. In this study, using cell-based assay systems in RAW264.7 murine macrophage cells, we found that baicalein significantly inhibited the receptor activator of NF-kappaB ligand (RANKL)-induced tartrate-resistance acid phosphatase (TRAP) activity and the formation of multinucleated osteoclasts in a dose-dependent manner. Interestingly, baicalein inhibited RANKL-induced activation of signaling molecules (Akt, ERK/MAP kinase and NF-kappaB) and mRNA expression of osteoclast-associated genes (TRAP, matrix metalloproteinase 9 and c-Src) and another transcription factors (c-Fos, Fra-2 and NFATc1). In addition, baicalein inhibited the bone resorptive activity of mature osteoclasts by inducing apoptosis. The inhibitory effects of baicalein on the formation of mouse bone marrow macrophage-derived osteoclasts and their bone resorptive activity were also observed. In conclusion, although further studies are needed to determine its biological efficacy and precise mechanism in bone, the present results demonstrated that baicalein has a potential to inhibit osteoclast differentiation and induce mature osteoclast apoptosis.
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PMID:Baicalein inhibits osteoclast differentiation and induces mature osteoclast apoptosis. 1878 94

We have previously shown that the nitrosylated flurbiprofen derivative HCT1026 inhibits bone resorption, both in vivo and in vitro, and that its mechanism of action is independent of nitric oxide release and prostaglandin synthesis inhibition. Here we describe the effects of HCT1026 on osteoclast formation, activity, survival and cell signalling in vitro. HCT1026 strongly inhibited osteoclast formation, activity and survival in murine osteoclast cultures, whereas macrophages and osteoblasts were unaffected. HCT1026 induced osteoclast apoptosis, and this was partially prevented by increasing the concentration of receptor activator of nuclear factor kappa B ligand (RANKL). This suggests that HCT1026 inhibits bone resorption by inhibiting the effects of RANKL. In agreement with this we found that HCT1026 inhibited RANKL-induced activation of the nuclear factor kappa B (NFkappaB) and extracellular signal-regulated kinase (ERK) pathways in both osteoclast and macrophage cultures, whereas its parent compound flurbiprofen did not. In addition, HCT1026 also inhibited tumor necrosis factor (TNF)-, interleukin-1 (IL1)- and LPS-induced signalling, but not macrophage colony stimulating factor induced signalling. The pathways that are inhibited by HCT1026 all share a similar kinase complex upstream of the NFkappaB and ERK pathways, and this is the most likely target for the actions of HCT1026. Although the rationale for the modification of flurbiprofen with a nitric oxide donor group was to prevent gastro-intestinal toxicity, the resulting compound HCT1026 gained unexpected additional cytokine-inhibitory properties. As RANKL, TNF and IL1 are all important mediators of inflammation and joint destruction, compounds like HCT1026 could represent a novel class of anti-inflammatory compounds.
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PMID:The nitrosylated flurbiprofen derivative HCT1026 inhibits cytokine-induced signalling through a novel mechanism of action. 1904 64


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