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)

RAF2 and TRAF5 are closely related members of the TRAF family of proteins. They are important signal transducers for a wide range of TNF receptor superfamily members, including TNFR1, TNFR2, CD40 and other lymphocyte costimulatory receptors, RANK/TRANCE-R, EDAR, LTbetaR, LMP-1 and IRE1. TRAF2 andTRAF5 therefore regulate diverse physiological roles, ranging from T and B cell signaling and inflammatory responses to organogenesis and cell survival. The major pathways mediated by TRAF2 and TRAF5 are the classical and alternative pathways of NF-kappaB activation, and MAPK and JNK activation. TRAF2 is heavily regulated by ubiquitin signals, and many of the signaling functions of TRAF2 are mediated through its RING domain and likely its own role as an E3 ubiquitin ligase.
 ...
PMID:Physiological roles and mechanisms of signaling by TRAF2 and TRAF5. 1763 15

Fusion of macrophages is an essential step in the differentiation of osteoclasts, which play a central role in the development and remodeling of bone. Osteoclasts are important mediators of bone loss, which leads, for example, to osteoporosis. Macrophage fusion receptor/signal regulatory protein alpha (MFR/SIRPalpha) and its ligand CD47, which are members of the Ig superfamily (IgSF), have been implicated in the fusion of macrophages. We show that CD200, which is not expressed in cells that belong to the myeloid lineage, is strongly expressed in macrophages at the onset of fusion. By contrast, the CD200 receptor (CD200R), which, like CD200, belongs to the IgSF, is expressed only in cells that belong to the myeloid lineage, including osteoclasts, and in CD4+ T cells. Osteoclasts from CD200-/- mice differentiated at a reduced rate. Activation of the NF-kappaB and MAP kinase signaling pathways downstream of RANK, a receptor that plays a central role in the differentiation of osteoclasts, was depressed in these cells. A soluble recombinant protein that included the extracellular domain of CD200 rescued the fusion of CD200-/- macrophages and their activation downstream of RANK. Conversely, addition of a soluble recombinant protein that included the extracellular domain of CD200R or short-hairpin RNA-mediated silencing of the expression of CD200R prevented fusion. Thus CD200 engagement of the CD200R at the initiation of macrophage fusion regulated further differentiation to osteoclasts. Consistent with in vitro observations, CD200-/- mice contained fewer osteoclasts and accumulated more bone than CD200+/+ mice. The CD200-CD200R axis is therefore a putative regulator of bone mass, via the formation of osteoclasts.
 ...
PMID:CD200 and its receptor, CD200R, modulate bone mass via the differentiation of osteoclasts. 1772 8

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.
 ...
PMID:High extracellular inorganic phosphate concentration inhibits RANK-RANKL signaling in osteoclast-like cells. 1789 87

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.
 ...
PMID:Interleukin-6 directly inhibits osteoclast differentiation by suppressing receptor activator of NF-kappaB signaling pathways. 1829 9

Paget's disease (PD) of bone is characterized by increased activity of large abnormal osteoclasts (OCLs) which contain paramyxoviral nuclear and cytoplasmic inclusions. MVNP gene expression has been shown to induce pagetic phenotype in OCLs. We previously characterized the osteoclast inhibitory peptide-1 (OIP-1/hSca) which inhibits OCL formation/bone resorption. OIP-1 is a glycophosphatidylinositol (GPI)-linked membrane protein containing a 79 amino acid extra cellular peptide and a 32 amino acid carboxy terminal GPI-linked peptide (c-peptide) which is critical for OCL inhibition. In this study, we demonstrate that OIP-1 c-peptide significantly decreased (43%) osteoclast differentiation of peripheral blood mononuclear cells from patients with PD. Also, OIP-1 treatment to normal human bone marrow mononuclear cells transduced with the MVNP inhibited (41%) osteoclast precursor (CFU-GM) growth in methyl-cellulose cultures. We further tested if OIP-1 overexpression in the OCL lineage in transgenic mice inhibits MVNP stimulated OCL formation. MVNP transduction and RANKL stimulation of OIP-1 mouse bone marrow cells showed a significant decrease (43%) in OCL formation and inhibition (38%) of bone resorption area compared to wild-type mice. Western blot analysis identified that OIP-1 decreased (3.5-fold) MVNP induced TRAF2 expression during OCL differentiation. MVNP or OIP-1 expression did not affect TRAF6 levels. Furthermore, OIP-1 expression resulted in a significant inhibition of MVNP stimulated ASK1, Rac1, c-Fos, p-JNK, and NFATc1 expression during OCL differentiation. These results suggest that OIP-1 inhibits MVNP induced pagetic OCL formation/activity through suppression of RANK signaling. Thus, OIP-1 may have therapeutic utility against excess bone resorption in patients with PD.
 ...
PMID:Osteoclast inhibitory peptide-1 (OIP-1) inhibits measles virus nucleocapsid protein stimulated osteoclast formation/activity. 1834 1

We have shown in two accompanying papers that TNF induces oscillations in (1) approximately 13% of the genome, and (2) the activation of MAP kinase and NF-kappaB signaling pathways. Here we aim to bridge oscillations in signal transduction activation to oscillations in genetic output. Specifically, we sought to study how these oscillations can combine in a ligand-specific manner at the level of the promoter to initiate gene transcription. We utilize the late onset gene CD38 as a model gene since it has previously been shown that TNF, but not the related cytokine RANK-L, induces its expression. We find that TNF-induced oscillations in p65 and p50 recruitment to the CD38 promoter correlated with recruitment of MAPK-induced AP-1 recruitment, as analyzed by quantitative ChIP analysis. Through re-ChIP analysis we show that a unique transcriptional complex is seen on the promoter at 3h post-TNF addition, corresponding to the onset of CD38 transcription, which is not seen in the basal state. Moreover, we show that RANK-L was unable to combinatorially recruit AP-1 and NF-kappaB transcription factors to the CD38 promoter, despite inducing the activation of both signaling pathways. These results, in sum with the two accompanying papers, constitute a new paradigm through which cells dynamically orchestrate signaling molecules to coordinate time-resolved gene transcription by the formation of novel time-specific transcriptional complexes.
 ...
PMID:TNF-induced oscillations in combinatorial transcription factor binding. 1838 44

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.
 ...
PMID:The 4-1BB ligand and 4-1BB expressed on osteoclast precursors enhance RANKL-induced osteoclastogenesis via bi-directional signaling. 1842 90

It has been reported previously that inhibitory kappaB kinase (IKK) supports osteoclastogenesis through NF-kappaB-mediated prevention of apoptosis. This finding suggests that the ligand for receptor activator of NF-kappaB (RANKL), the master osteoclastogenic cytokine, induces apoptosis of osteoclast precursors (OCPs) in the absence of IKKbeta/NF-kappaB competency. To validate this hypothesis, we sought to determine the pro-apoptotic signaling factors induced by RANKL in IKKbeta-null osteoclast OCPs and to rescue osteoclast differentiation in the absence of IKKbeta through their inhibition. To accomplish this, we generated mice that lack IKKbeta in multiple hematopoietic lineages, including OCPs. We found that these mice possess both in vitro and in vivo defects in osteoclast generation, in concurrence with previous reports, and that this defect is a result of susceptibility to RANKL-mediated apoptosis as a result of gain-of-function of JNK activation. We demonstrate that differentiation of OCPs depends on IKKbeta because reduced IKKbeta mRNA expression correlates with impaired induction of osteoclast differentiation markers in response to RANKL stimulation. We further show that fine-tuned inhibition of JNK activation in these cells inhibits RANKL-induced apoptosis and restores the ability of IKKbeta-null OCPs to become mature osteoclasts. Our data highlight the pro-osteoclastogenic and anti-apoptotic roles of IKKbeta in OCPs and identify a pro-apoptotic mechanism activated within the RANK signalosome.
 ...
PMID:Defective osteoclastogenesis by IKKbeta-null precursors is a result of receptor activator of NF-kappaB ligand (RANKL)-induced JNK-dependent apoptosis and impaired differentiation. 1856 79

Phospholipase Cgamma2 (PLCgamma2) is an important signaling effector of multiple receptors in the immune system. Here we show that PLCgamma2-deficient mice displayed impaired lymph node organogenesis but normal splenic structure and Peyer's patches. Receptor activator of NF-kappaB ligand (RANKL) is a tumor necrosis factor family cytokine and is essential for lymph node organogenesis. Importantly, PLCgamma2 deficiency severely impaired RANKL signaling, resulting in marked reduction of RANKL-induced activation of MAPKs, p38 and JNK, but not ERK. The lack of PLCgamma2 markedly diminished RANKL-induced activation of NF-kappaB, AP-1, and NFATc1. Moreover, PLCgamma2 deficiency impaired RANKL-mediated biological function, leading to failure of the PLCgamma2-deficient bone marrow macrophage precursors to differentiate into osteoclasts after RANKL stimulation. Re-introduction of PLCgamma2 but not PLCgamma1 restores RANKL-mediated osteoclast differentiation of PLCgamma2-deficient bone marrow-derived monocyte/macrophage. Taken together, PLCgamma2 is essential for RANK signaling, and its deficiency leads to defective lymph node organogenesis and osteoclast differentiation.
 ...
PMID:Phospholipase Cgamma2 mediates RANKL-stimulated lymph node organogenesis and osteoclastogenesis. 1872 19

Understanding the mechanisms of osteoclastogenesis is crucial for developing new drugs to treat diseases associated with bone loss, such as osteoporosis. Here we report that the C-C chemokine receptor-2 (CCR2) is crucially involved in balancing bone mass. CCR2-knockout mice have high bone mass owing to a decrease in number, size and function of osteoclasts. In normal mice, activation of CCR2 in osteoclast progenitor cells results in both nuclear factor-kappaB (NF-kappaB) and extracellular signal-related kinase 1 and 2 (ERK1/2) signaling but not that of p38 mitogen-activated protein kinase or c-Jun N-terminal kinase. The induction of NF-kappaB and ERK1/2 signaling in turn leads to increased surface expression of receptor activator of NF-kappaB (RANK, encoded by Tnfrsf11a), making the progenitor cells more susceptible to RANK ligand-induced osteoclastogenesis. In ovariectomized mice, a model of postmenopausal osteoporosis, CCR2 is upregulated on wild-type preosteoclasts, thus increasing the surface expression of RANK on these cells and their osteoclastogenic potential, whereas CCR2-knockout mice are resistant to ovariectomy-induced bone loss. These data reveal a previously undescribed pathway by which RANK, osteoclasts and bone homeostasis are regulated in health and disease.
 ...
PMID:Estrogen-dependent and C-C chemokine receptor-2-dependent pathways determine osteoclast behavior in osteoporosis. 1933 10


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>