The Experts below are selected from a list of 23514 Experts worldwide ranked by ideXlab platform
Yousef Abuamer - One of the best experts on this subject based on the ideXlab platform.
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tumor necrosis factor α tnf stimulates rankl induced Osteoclastogenesis via coupling of tnf type 1 receptor and rank signaling pathways
Journal of Biological Chemistry, 2001Co-Authors: Yan-hong Zhang, Antoinette Heulsmann, M M Tondravi, Aditi Mukherjee, Yousef AbuamerAbstract:Abstract Tumor necrosis factor-α (TNF) and the ligand for receptor activator of NF-κB (RANKL) are abundant in sites of inflammatory bone erosion. Because these cytokines are potent osteoclastogenic factors and because their signaling pathways are considerably overlapping, we postulated that under pro-inflammatory conditions RANKL and TNF might synergistically orchestrate enhanced Osteoclastogenesis via cooperative mechanisms. We found TNF, via TNF type 1 receptor (TNFr1), prompts robust Osteoclastogenesis by osteoclast precursors pretreated with RANKL, and deletion of TNFr1 abrogates this response. Enhanced Osteoclastogenesis is associated with high expression of otherwise TNF and RANKL-induced mediators, including c-Src, TRAF2, TRAF6, and MEKK-1, levels of which were notably reduced in TNFr1 knockouts. Recruitment of TRAFs and MEKK1 leads to activation of downstream pathways, primarily IκB/NF-κB, ERKs, and cJun/AP-1. Consistent with impaired Osteoclastogenesis and reduced expression of TRAFs and MEKK1, we found that phosphorylation and activation of IκB, NF-κB, ERKs, and cJun/AP-1 are severely reduced in RANKL-treated TNFr1-null osteoclast precursors compared with wild type counterparts. Finally, we found that TNF and RANKL synergistically up-regulate RANK expression in wild type precursors, whereas basal and stimulated levels of RANK are significantly lower in TNFr1 knockout cells. Our data suggest that exuberant TNF-induced osteoclastogensis is the result of coupling between RANK and TNFr1 and is dependent upon signals transmitted by the latter receptor.
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tumor necrosis factor alpha tnf stimulates rankl induced Osteoclastogenesis via coupling of tnf type 1 receptor and rank signaling pathways
Journal of Biological Chemistry, 2001Co-Authors: Yan-hong Zhang, Antoinette Heulsmann, M M Tondravi, Aditi Mukherjee, Yousef AbuamerAbstract:Abstract Tumor necrosis factor-α (TNF) and the ligand for receptor activator of NF-κB (RANKL) are abundant in sites of inflammatory bone erosion. Because these cytokines are potent osteoclastogenic factors and because their signaling pathways are considerably overlapping, we postulated that under pro-inflammatory conditions RANKL and TNF might synergistically orchestrate enhanced Osteoclastogenesis via cooperative mechanisms. We found TNF, via TNF type 1 receptor (TNFr1), prompts robust Osteoclastogenesis by osteoclast precursors pretreated with RANKL, and deletion of TNFr1 abrogates this response. Enhanced Osteoclastogenesis is associated with high expression of otherwise TNF and RANKL-induced mediators, including c-Src, TRAF2, TRAF6, and MEKK-1, levels of which were notably reduced in TNFr1 knockouts. Recruitment of TRAFs and MEKK1 leads to activation of downstream pathways, primarily IκB/NF-κB, ERKs, and cJun/AP-1. Consistent with impaired Osteoclastogenesis and reduced expression of TRAFs and MEKK1, we found that phosphorylation and activation of IκB, NF-κB, ERKs, and cJun/AP-1 are severely reduced in RANKL-treated TNFr1-null osteoclast precursors compared with wild type counterparts. Finally, we found that TNF and RANKL synergistically up-regulate RANK expression in wild type precursors, whereas basal and stimulated levels of RANK are significantly lower in TNFr1 knockout cells. Our data suggest that exuberant TNF-induced osteoclastogensis is the result of coupling between RANK and TNFr1 and is dependent upon signals transmitted by the latter receptor.
Lionel B. Ivashkiv - One of the best experts on this subject based on the ideXlab platform.
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RBP-J–Regulated miR-182 Promotes TNF-α–Induced Osteoclastogenesis
Journal of Immunology, 2016Co-Authors: Christine H. Miller, Sinead M. Smith, Mahmoud Elguindy, Tuo Zhang, Jenny Xiang, Xiaoyu Hu, Lionel B. Ivashkiv, Baohong ZhaoAbstract:Increased Osteoclastogenesis is responsible for osteolysis, which is a severe consequence of inflammatory diseases associated with bone destruction, such as rheumatoid arthritis and periodontitis. The mechanisms that limit Osteoclastogenesis under inflammatory conditions are largely unknown. We previously identified transcription factor RBP-J as a key negative regulator that restrains TNF-α–induced Osteoclastogenesis and inflammatory bone resorption. In this study, we tested whether RBP-J suppresses inflammatory Osteoclastogenesis by regulating the expression of microRNAs (miRNAs) important for this process. Using high-throughput sequencing of miRNAs, we obtained the first, to our knowledge, genome-wide profile of miRNA expression induced by TNF-α in mouse bone marrow–derived macrophages/osteoclast precursors during inflammatory Osteoclastogenesis. Furthermore, we identified miR-182 as a novel miRNA that promotes inflammatory Osteoclastogenesis driven by TNF-α and whose expression is suppressed by RBP-J. Downregulation of miR-182 dramatically suppressed the enhanced Osteoclastogenesis program induced by TNF-α in RBP-J–deficient cells. Complementary loss- and gain-of-function approaches showed that miR-182 is a positive regulator of osteoclastogenic transcription factors NFATc1 and B lymphocyte–induced maturation protein-1. Moreover, we identified that direct miR-182 targets, Foxo3 and Maml1, play important inhibitory roles in TNF-α–mediated Osteoclastogenesis. Thus, RBP-J–regulated miR-182 promotes TNF-α–induced Osteoclastogenesis via inhibition of Foxo3 and Maml1. Suppression of miR-182 by RBP-J serves as an important mechanism that restrains TNF-α–induced Osteoclastogenesis. Our results provide a novel miRNA-mediated mechanism by which RBP-J inhibits Osteoclastogenesis and suggest that targeting of the newly described RBP-J–miR-182–Foxo3/Maml1 axis may represent an effective therapeutic approach to suppress inflammatory Osteoclastogenesis and bone resorption.
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cutting edge ezh2 promotes Osteoclastogenesis by epigenetic silencing of the negative regulator irf8
Journal of Immunology, 2016Co-Authors: Celestia Fang, Lionel B. Ivashkiv, Baohong Zhao, Yu Qiao, Koichi Murata, Kyunghyun ParkminAbstract:Osteoclasts are resorptive cells that are important for homeostatic bone remodeling and pathological bone resorption. Emerging evidence suggests an important role for epigenetic mechanisms in Osteoclastogenesis. A recent study showed that epigenetic silencing of the negative regulator of Osteoclastogenesis Irf8 by DNA methylation is required for osteoclast differentiation. In this study, we investigated the role of EZH2, which epigenetically silences gene expression by histone methylation, in Osteoclastogenesis. Inhibition of EZH2 by the small molecule GSK126, or decreasing its expression using antisense oligonucleotides, impeded osteoclast differentiation. Mechanistically, EZH2 was recruited to the IRF8 promoter after RANKL stimulation to deposit the negative histone mark H3K27me3 and downregulate IRF8 expression. GSK126 attenuated bone loss in the ovariectomy mouse model of postmenopausal osteoporosis. Our findings provide evidence for an additional mechanism of epigenetic IRF8 silencing during Osteoclastogenesis that likely works cooperatively with DNA methylation, further emphasizing the importance of IRF8 as a negative regulator of Osteoclastogenesis.
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tnf induced Osteoclastogenesis and inflammatory bone resorption are inhibited by transcription factor rbp j
Journal of Experimental Medicine, 2012Co-Authors: Baohong Zhao, Xiaoyu Hu, Lionel B. Ivashkiv, Shannon N Grimes, Susan LiAbstract:Tumor necrosis factor (TNF) plays a key role in the pathogenesis of inflammatory bone resorption and associated morbidity in diseases such as rheumatoid arthritis and periodontitis. Mechanisms that regulate the direct osteoclastogenic properties of TNF to limit pathological bone resorption in inflammatory settings are mostly unknown. Here, we show that the transcription factor recombinant recognition sequence binding protein at the Jκ site (RBP-J) strongly suppresses TNF-induced Osteoclastogenesis and inflammatory bone resorption, but has minimal effects on physiological bone remodeling. Myeloid-specific deletion of RBP-J converted TNF into a potent osteoclastogenic factor that could function independently of receptor activator of NF-κB (RANK) signaling. In the absence of RBP-J, TNF effectively induced Osteoclastogenesis and bone resorption in RANK-deficient mice. Activation of RBP-J selectively in osteoclast precursors suppressed inflammatory Osteoclastogenesis and arthritic bone resorption. Mechanistically, RBP-J suppressed induction of the master regulator of Osteoclastogenesis (nuclear factor of activated T cells, cytoplasmic 1) by attenuating c-Fos activation and suppressing induction of B lymphocyte–induced maturation protein-1, thereby preventing the down-regulation of transcriptional repressors such as IRF-8 that block osteoclast differentiation. Thus, RBP-J regulates the balance between activating and repressive signals that regulate Osteoclastogenesis. These findings identify RBP-J as a key upstream negative regulator of Osteoclastogenesis that restrains excessive bone resorption in inflammatory settings.
Yan-hong Zhang - One of the best experts on this subject based on the ideXlab platform.
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Ubiquitin-like domain of IKKβ regulates Osteoclastogenesis and osteolysis.
Calcified Tissue International, 2013Co-Authors: Yan-hong Zhang, Jesse E. Otero, Yousef Abu-amerAbstract:The transcription factor NF-κB family is central for Osteoclastogenesis and inflammatory osteolysis. Activation of NF-κB dimers is regulated by a kinase complex predominantly containing IKKα (IKK1), IKKβ (IKK2), and a regulatory subunit, IKKγ/NEMO. IKKα and IKKβ catalyze the cytoplasmic liberation and nuclear translocation of various NF-κB subunits. The requirement of IKKα and IKKβ for normal bone homeostasis has been established. Congruently, mice devoid of IKKα or IKKβ exhibit in vitro and in vivo defects in Osteoclastogenesis, and IKKβ-null mice are refractory to inflammatory arthritis and osteolysis. To better understand the molecular mechanism underlying IKKβ function in bone homeostasis and bone pathologies, we conducted structure–function analysis to determine IKKβ functional domains in osteoclasts. IKKβ encompasses several domains, of which the ubiquitination-like domain (ULD) has been shown essential for IKKβ activation. In this study, we examined the role of ULD in IKKβ-mediated NF-κB activation in osteoclast precursors and its contribution to Osteoclastogenesis and osteolysis. We generated and virally introduced IKKβ in which the ULD domain has been deleted (IKKβ∆ULD) into osteoclast progenitors. The results show that deletion of ULD diminishes IKKβ activity and that IKKβ∆ULD strongly inhibits Osteoclastogenesis. In addition, unlike wild type (WT)-IKKβ, IKKβ∆ULD fail to restore RANKL-induced Osteoclastogenesis by IKKβ-null precursors. Finally, we provide evidence that IKKβ∆ULD blocks inflammatory osteolysis in a model of murine calvarial osteolysis. Thus, we identified the ULD as crucial for IKKβ activity and Osteoclastogenesis and found that ULD-deficient IKKβ is a potent inhibitor of Osteoclastogenesis and osteolysis.
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tumor necrosis factor α tnf stimulates rankl induced Osteoclastogenesis via coupling of tnf type 1 receptor and rank signaling pathways
Journal of Biological Chemistry, 2001Co-Authors: Yan-hong Zhang, Antoinette Heulsmann, M M Tondravi, Aditi Mukherjee, Yousef AbuamerAbstract:Abstract Tumor necrosis factor-α (TNF) and the ligand for receptor activator of NF-κB (RANKL) are abundant in sites of inflammatory bone erosion. Because these cytokines are potent osteoclastogenic factors and because their signaling pathways are considerably overlapping, we postulated that under pro-inflammatory conditions RANKL and TNF might synergistically orchestrate enhanced Osteoclastogenesis via cooperative mechanisms. We found TNF, via TNF type 1 receptor (TNFr1), prompts robust Osteoclastogenesis by osteoclast precursors pretreated with RANKL, and deletion of TNFr1 abrogates this response. Enhanced Osteoclastogenesis is associated with high expression of otherwise TNF and RANKL-induced mediators, including c-Src, TRAF2, TRAF6, and MEKK-1, levels of which were notably reduced in TNFr1 knockouts. Recruitment of TRAFs and MEKK1 leads to activation of downstream pathways, primarily IκB/NF-κB, ERKs, and cJun/AP-1. Consistent with impaired Osteoclastogenesis and reduced expression of TRAFs and MEKK1, we found that phosphorylation and activation of IκB, NF-κB, ERKs, and cJun/AP-1 are severely reduced in RANKL-treated TNFr1-null osteoclast precursors compared with wild type counterparts. Finally, we found that TNF and RANKL synergistically up-regulate RANK expression in wild type precursors, whereas basal and stimulated levels of RANK are significantly lower in TNFr1 knockout cells. Our data suggest that exuberant TNF-induced osteoclastogensis is the result of coupling between RANK and TNFr1 and is dependent upon signals transmitted by the latter receptor.
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tumor necrosis factor alpha tnf stimulates rankl induced Osteoclastogenesis via coupling of tnf type 1 receptor and rank signaling pathways
Journal of Biological Chemistry, 2001Co-Authors: Yan-hong Zhang, Antoinette Heulsmann, M M Tondravi, Aditi Mukherjee, Yousef AbuamerAbstract:Abstract Tumor necrosis factor-α (TNF) and the ligand for receptor activator of NF-κB (RANKL) are abundant in sites of inflammatory bone erosion. Because these cytokines are potent osteoclastogenic factors and because their signaling pathways are considerably overlapping, we postulated that under pro-inflammatory conditions RANKL and TNF might synergistically orchestrate enhanced Osteoclastogenesis via cooperative mechanisms. We found TNF, via TNF type 1 receptor (TNFr1), prompts robust Osteoclastogenesis by osteoclast precursors pretreated with RANKL, and deletion of TNFr1 abrogates this response. Enhanced Osteoclastogenesis is associated with high expression of otherwise TNF and RANKL-induced mediators, including c-Src, TRAF2, TRAF6, and MEKK-1, levels of which were notably reduced in TNFr1 knockouts. Recruitment of TRAFs and MEKK1 leads to activation of downstream pathways, primarily IκB/NF-κB, ERKs, and cJun/AP-1. Consistent with impaired Osteoclastogenesis and reduced expression of TRAFs and MEKK1, we found that phosphorylation and activation of IκB, NF-κB, ERKs, and cJun/AP-1 are severely reduced in RANKL-treated TNFr1-null osteoclast precursors compared with wild type counterparts. Finally, we found that TNF and RANKL synergistically up-regulate RANK expression in wild type precursors, whereas basal and stimulated levels of RANK are significantly lower in TNFr1 knockout cells. Our data suggest that exuberant TNF-induced osteoclastogensis is the result of coupling between RANK and TNFr1 and is dependent upon signals transmitted by the latter receptor.
M M Tondravi - One of the best experts on this subject based on the ideXlab platform.
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tumor necrosis factor α tnf stimulates rankl induced Osteoclastogenesis via coupling of tnf type 1 receptor and rank signaling pathways
Journal of Biological Chemistry, 2001Co-Authors: Yan-hong Zhang, Antoinette Heulsmann, M M Tondravi, Aditi Mukherjee, Yousef AbuamerAbstract:Abstract Tumor necrosis factor-α (TNF) and the ligand for receptor activator of NF-κB (RANKL) are abundant in sites of inflammatory bone erosion. Because these cytokines are potent osteoclastogenic factors and because their signaling pathways are considerably overlapping, we postulated that under pro-inflammatory conditions RANKL and TNF might synergistically orchestrate enhanced Osteoclastogenesis via cooperative mechanisms. We found TNF, via TNF type 1 receptor (TNFr1), prompts robust Osteoclastogenesis by osteoclast precursors pretreated with RANKL, and deletion of TNFr1 abrogates this response. Enhanced Osteoclastogenesis is associated with high expression of otherwise TNF and RANKL-induced mediators, including c-Src, TRAF2, TRAF6, and MEKK-1, levels of which were notably reduced in TNFr1 knockouts. Recruitment of TRAFs and MEKK1 leads to activation of downstream pathways, primarily IκB/NF-κB, ERKs, and cJun/AP-1. Consistent with impaired Osteoclastogenesis and reduced expression of TRAFs and MEKK1, we found that phosphorylation and activation of IκB, NF-κB, ERKs, and cJun/AP-1 are severely reduced in RANKL-treated TNFr1-null osteoclast precursors compared with wild type counterparts. Finally, we found that TNF and RANKL synergistically up-regulate RANK expression in wild type precursors, whereas basal and stimulated levels of RANK are significantly lower in TNFr1 knockout cells. Our data suggest that exuberant TNF-induced osteoclastogensis is the result of coupling between RANK and TNFr1 and is dependent upon signals transmitted by the latter receptor.
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tumor necrosis factor alpha tnf stimulates rankl induced Osteoclastogenesis via coupling of tnf type 1 receptor and rank signaling pathways
Journal of Biological Chemistry, 2001Co-Authors: Yan-hong Zhang, Antoinette Heulsmann, M M Tondravi, Aditi Mukherjee, Yousef AbuamerAbstract:Abstract Tumor necrosis factor-α (TNF) and the ligand for receptor activator of NF-κB (RANKL) are abundant in sites of inflammatory bone erosion. Because these cytokines are potent osteoclastogenic factors and because their signaling pathways are considerably overlapping, we postulated that under pro-inflammatory conditions RANKL and TNF might synergistically orchestrate enhanced Osteoclastogenesis via cooperative mechanisms. We found TNF, via TNF type 1 receptor (TNFr1), prompts robust Osteoclastogenesis by osteoclast precursors pretreated with RANKL, and deletion of TNFr1 abrogates this response. Enhanced Osteoclastogenesis is associated with high expression of otherwise TNF and RANKL-induced mediators, including c-Src, TRAF2, TRAF6, and MEKK-1, levels of which were notably reduced in TNFr1 knockouts. Recruitment of TRAFs and MEKK1 leads to activation of downstream pathways, primarily IκB/NF-κB, ERKs, and cJun/AP-1. Consistent with impaired Osteoclastogenesis and reduced expression of TRAFs and MEKK1, we found that phosphorylation and activation of IκB, NF-κB, ERKs, and cJun/AP-1 are severely reduced in RANKL-treated TNFr1-null osteoclast precursors compared with wild type counterparts. Finally, we found that TNF and RANKL synergistically up-regulate RANK expression in wild type precursors, whereas basal and stimulated levels of RANK are significantly lower in TNFr1 knockout cells. Our data suggest that exuberant TNF-induced osteoclastogensis is the result of coupling between RANK and TNFr1 and is dependent upon signals transmitted by the latter receptor.
Antoinette Heulsmann - One of the best experts on this subject based on the ideXlab platform.
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tumor necrosis factor α tnf stimulates rankl induced Osteoclastogenesis via coupling of tnf type 1 receptor and rank signaling pathways
Journal of Biological Chemistry, 2001Co-Authors: Yan-hong Zhang, Antoinette Heulsmann, M M Tondravi, Aditi Mukherjee, Yousef AbuamerAbstract:Abstract Tumor necrosis factor-α (TNF) and the ligand for receptor activator of NF-κB (RANKL) are abundant in sites of inflammatory bone erosion. Because these cytokines are potent osteoclastogenic factors and because their signaling pathways are considerably overlapping, we postulated that under pro-inflammatory conditions RANKL and TNF might synergistically orchestrate enhanced Osteoclastogenesis via cooperative mechanisms. We found TNF, via TNF type 1 receptor (TNFr1), prompts robust Osteoclastogenesis by osteoclast precursors pretreated with RANKL, and deletion of TNFr1 abrogates this response. Enhanced Osteoclastogenesis is associated with high expression of otherwise TNF and RANKL-induced mediators, including c-Src, TRAF2, TRAF6, and MEKK-1, levels of which were notably reduced in TNFr1 knockouts. Recruitment of TRAFs and MEKK1 leads to activation of downstream pathways, primarily IκB/NF-κB, ERKs, and cJun/AP-1. Consistent with impaired Osteoclastogenesis and reduced expression of TRAFs and MEKK1, we found that phosphorylation and activation of IκB, NF-κB, ERKs, and cJun/AP-1 are severely reduced in RANKL-treated TNFr1-null osteoclast precursors compared with wild type counterparts. Finally, we found that TNF and RANKL synergistically up-regulate RANK expression in wild type precursors, whereas basal and stimulated levels of RANK are significantly lower in TNFr1 knockout cells. Our data suggest that exuberant TNF-induced osteoclastogensis is the result of coupling between RANK and TNFr1 and is dependent upon signals transmitted by the latter receptor.
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tumor necrosis factor alpha tnf stimulates rankl induced Osteoclastogenesis via coupling of tnf type 1 receptor and rank signaling pathways
Journal of Biological Chemistry, 2001Co-Authors: Yan-hong Zhang, Antoinette Heulsmann, M M Tondravi, Aditi Mukherjee, Yousef AbuamerAbstract:Abstract Tumor necrosis factor-α (TNF) and the ligand for receptor activator of NF-κB (RANKL) are abundant in sites of inflammatory bone erosion. Because these cytokines are potent osteoclastogenic factors and because their signaling pathways are considerably overlapping, we postulated that under pro-inflammatory conditions RANKL and TNF might synergistically orchestrate enhanced Osteoclastogenesis via cooperative mechanisms. We found TNF, via TNF type 1 receptor (TNFr1), prompts robust Osteoclastogenesis by osteoclast precursors pretreated with RANKL, and deletion of TNFr1 abrogates this response. Enhanced Osteoclastogenesis is associated with high expression of otherwise TNF and RANKL-induced mediators, including c-Src, TRAF2, TRAF6, and MEKK-1, levels of which were notably reduced in TNFr1 knockouts. Recruitment of TRAFs and MEKK1 leads to activation of downstream pathways, primarily IκB/NF-κB, ERKs, and cJun/AP-1. Consistent with impaired Osteoclastogenesis and reduced expression of TRAFs and MEKK1, we found that phosphorylation and activation of IκB, NF-κB, ERKs, and cJun/AP-1 are severely reduced in RANKL-treated TNFr1-null osteoclast precursors compared with wild type counterparts. Finally, we found that TNF and RANKL synergistically up-regulate RANK expression in wild type precursors, whereas basal and stimulated levels of RANK are significantly lower in TNFr1 knockout cells. Our data suggest that exuberant TNF-induced osteoclastogensis is the result of coupling between RANK and TNFr1 and is dependent upon signals transmitted by the latter receptor.
