scholarly journals Ets-2 Propagates IL-6 Trans-Signaling Mediated Osteoclast-Like Changes in Human Rheumatoid Arthritis Synovial Fibroblast

2021 ◽  
Vol 12 ◽  
Author(s):  
Anil K. Singh ◽  
Mahamudul Haque ◽  
Bhanupriya Madarampalli ◽  
Yuanyuan Shi ◽  
Benjamin J. Wildman ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Transcriptional Activation ◽  
Molecular Mechanisms ◽  
Nuclear Translocation ◽  
Bone Destruction ◽  
Metabolic Reprogramming ◽  
Mass Spectrometry Analysis ◽  
Tartrate Resistant Acid Phosphatase ◽  
Positive Staining ◽  
Human Rheumatoid Arthritis

Rheumatoid arthritis synovial fibroblasts (RASFs) contribute to synovial inflammation and bone destruction by producing a pleiotropic cytokine interleukin-6 (IL-6). However, the molecular mechanisms through which IL-6 propels RASFs to contribute to bone loss are not fully understood. In the present study, we investigated the effect of IL-6 and IL-6 receptor (IL-6/IL-6R)-induced trans-signaling in human RASFs. IL-6 trans-signaling caused a significant increase in tartrate-resistant acid phosphatase (TRAP)-positive staining in RASFs and enhanced pit formation by ~3-fold in the osteogenic surface in vitro. IL-6/IL-6R caused dose-dependent increase in expression and nuclear translocation of transcription factor Ets2, which correlated with the expression of osteoclast-specific signature proteins RANKL, cathepsin B (CTSB), and cathepsin K (CTSK) in RASFs. Chromatin immunoprecipitation (ChIP) analysis of CTSB and CTSK promoters showed direct Ets2 binding and transcriptional activation upon IL-6/IL-6R stimulation. Knockdown of Ets2 significantly inhibited IL-6/IL-6R-induced RANKL, CTSB, and CTSK expression and TRAP staining in RASFs and suppressed markers of RASF invasive phenotype such as Thy1 and podoplanin (PDPN). Mass spectrometry analysis of the secretome identified 113 proteins produced by RASFs uniquely in response to IL-6/IL-6R that bioinformatically predicted its impact on metabolic reprogramming towards an osteoclast-like phenotype. These findings identified the role of Ets2 in IL-6 trans-signaling induced molecular reprogramming of RASFs to osteoclast-like cells and may contribute to RASF heterogeneity.

scholarly journals WTIP upregulates FOXO3a and induces apoptosis through PUMA in acute myeloid leukemia

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Yunqi Zhu ◽  
Xiangmin Tong ◽  
Ying Wang ◽  
Xiaoya Lu
Keyword(s):  
Acute Myeloid Leukemia ◽  
Tumor Suppressor ◽  
Transcriptional Activation ◽  
Myeloid Leukemia ◽  
Molecular Mechanisms ◽  
Nuclear Translocation ◽  
Hematologic Malignancy ◽  
Apoptotic Pathway ◽  
Acute Myeloid

AbstractAcute myeloid leukemia (AML) is an aggressive and heterogeneous clonal hematologic malignancy for which novel therapeutic targets and strategies are required. Emerging evidence suggests that WTIP is a candidate tumor suppressor. However, the molecular mechanisms of WTIP in leukemogenesis have not been explored. Here, we report that WTIP expression is significantly reduced both in AML cell lines and clinical specimens compared with normal controls, and low levels of WTIP correlate with decreased overall survival in AML patients. Overexpression of WTIP inhibits cell proliferation and induces apoptosis both in vitro and in vivo. Mechanistic studies reveal that the apoptotic function of WTIP is mediated by upregulation and nuclear translocation of FOXO3a, a member of Forkhead box O (FOXO) transcription factors involved in tumor suppression. We further demonstrate that WTIP interacts with FOXO3a and transcriptionally activates FOXO3a. Upon transcriptional activation of FOXO3a, its downstream target PUMA is increased, leading to activation of the intrinsic apoptotic pathway. Collectively, our results suggest that WTIP is a tumor suppressor and a potential target for therapeutic intervention in AML.

Advancement of Natural Compounds as Anti- Rheumatoid Arthritis Agents: Focus on Their Mechanism of Actions

2021 ◽  
Vol 21 ◽  
Author(s):  
Huanghe Yu ◽  
Yixing Qiu ◽  
Shumaila Tasneem ◽  
Muhammad Daniyal ◽  
Bin Li ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Molecular Mechanisms ◽  
Bone Destruction ◽  
Inflammatory Cells ◽  
Chronic Inflammatory Disease ◽  
Mechanisms Of Action ◽  
Pannus Formation ◽  
Synovial Hyperplasia ◽  
Naturally Occurring ◽  
Natural Plants

: Rheumatoid arthritis (RA) is a chronic inflammatory disease categorized by infiltration of inflammatory cells, synovial hyperplasia, pannus formation and bone destruction, leading to disability worldwide. Despite the presence of the commercial availability of anti-RA agent on the market, the application of these drugs is limited due to its side effects. Anti-rheumatic drugs are more effective and safer being investigated by many researchers, especially, natural products with anti-RA have been identified and the underlying molecular mechanisms of action of novel and known compounds have been reported. In this review, we intend to provide a comprehensive view and updated on naturally occurring compounds known and novel that has the effect of anti-RA, and then classify them according to their molecular mechanisms of action in regulating the anti-RA lane main. The safety of compounds from natural plants and western medicine has also been briefly compared. In addition, the clinical trials with anti-RA compounds isolated from natural plants in RA were also summarized in this manuscript.

scholarly journals Metabolic regulation of exercise-induced angiogenesis

2019 ◽  
Vol 1 (1) ◽  
pp. H1-H8 ◽  
Author(s):  
Tatiane Gorski ◽  
Katrien De Bock
Keyword(s):  
Skeletal Muscle ◽  
Transcriptional Activation ◽  
Metabolic Regulation ◽  
Molecular Mechanisms ◽  
Metabolic Reprogramming ◽  
Sirtuin 1 ◽  
Peroxisome Proliferator ◽  
Valuable Insight ◽  
Peroxisome Proliferator Activated Receptor ◽  
Exercise Induced

Skeletal muscle relies on an ingenious network of blood vessels, which ensures optimal oxygen and nutrient supply. An increase in muscle vascularization is an early adaptive event to exercise training, but the cellular and molecular mechanisms underlying exercise-induced blood vessel formation are not completely clear. In this review, we provide a concise overview on how exercise-induced alterations in muscle metabolism can evoke metabolic changes in endothelial cells (ECs) that drive muscle angiogenesis. In skeletal muscle, angiogenesis can occur via sprouting and splitting angiogenesis and is dependent on vascular endothelial growth factor (VEGF) signaling. In the resting muscle, VEGF levels are controlled by the estrogen-related receptor γ (ERRγ). Upon exercise, the transcriptional coactivator peroxisome-proliferator-activated receptor-γ coactivator-1α (PGC1α) orchestrates several adaptations to endurance exercise within muscle fibers and simultaneously promotes transcriptional activation of Vegf expression and increased muscle capillary density. While ECs are highly glycolytic and change their metabolism during sprouting angiogenesis in development and disease, a similar role for EC metabolism in exercise-induced angiogenesis in skeletal muscle remains to be elucidated. Nonetheless, recent studies have illustrated the importance of endothelial hydrogen sulfide and sirtuin 1 (SIRT1) activity for exercise-induced angiogenesis, suggesting that EC metabolic reprogramming may be fundamental in this process. We hypothesize that the exercise-induced angiogenic response can also be modulated by metabolic crosstalk between muscle and the endothelium. Defining the underlying molecular mechanisms responsible for skeletal muscle angiogenesis in response to exercise will yield valuable insight into metabolic regulation as well as the determinants of exercise performance.

scholarly journals SUMOylation Is Required for ERK5 Nuclear Translocation and ERK5-Mediated Cancer Cell Proliferation

2020 ◽  
Vol 21 (6) ◽  
pp. 2203 ◽  
Author(s):  
Tatiana Erazo ◽  
Sergio Espinosa-Gil ◽  
Nora Diéguez-Martínez ◽  
Néstor Gómez ◽  
Jose M Lizcano
Keyword(s):  
Cell Proliferation ◽  
Cancer Cell ◽  
Nuclear Localization ◽  
Transcriptional Activation ◽  
Molecular Mechanisms ◽  
Nuclear Translocation ◽  
Kinase Domain ◽  
Cancer Cell Proliferation ◽  
Transcriptional Activation Domain ◽  
Nuclear Shuttling

The MAP kinase ERK5 contains an N-terminal kinase domain and a unique C-terminal tail including a nuclear localization signal and a transcriptional activation domain. ERK5 is activated in response to growth factors and stresses and regulates transcription at the nucleus by either phosphorylation or interaction with transcription factors. MEK5-ERK5 pathway plays an important role regulating cancer cell proliferation and survival. Therefore, it is important to define the precise molecular mechanisms implicated in ERK5 nucleo-cytoplasmic shuttling. We previously described that the molecular chaperone Hsp90 stabilizes and anchors ERK5 at the cytosol and that ERK5 nuclear shuttling requires Hsp90 dissociation. Here, we show that MEK5 or overexpression of Cdc37—mechanisms that increase nuclear ERK5—induced ERK5 Small Ubiquitin-related Modifier (SUMO)-2 modification at residues Lys6/Lys22 in cancer cells. Furthermore, mutation of these SUMO sites abolished the ability of ERK5 to translocate to the nucleus and to promote prostatic cancer PC-3 cell proliferation. We also show that overexpression of the SUMO protease SENP2 completely abolished endogenous ERK5 nuclear localization in response to epidermal growth factor (EGF) stimulation. These results allow us to propose a more precise mechanism: in response to MEK5 activation, ERK5 SUMOylation favors the dissociation of Hsp90 from the complex, allowing ERK5 nuclear shuttling and activation of the transcription.

scholarly journals Mutant p53 Gain-of-Function: Role in Cancer Development, Progression, and Therapeutic Approaches

2021 ◽  
Vol 8 ◽  
Author(s):  
Eduardo Alvarado-Ortiz ◽  
Karen Griselda de la Cruz-López ◽  
Jared Becerril-Rico ◽  
Miguel Angel Sarabia-Sánchez ◽  
Elizabeth Ortiz-Sánchez ◽  
...  
Keyword(s):  
Transcriptional Activation ◽  
Molecular Mechanisms ◽  
Driving Forces ◽  
Mevalonate Pathway ◽  
Regulatory Element ◽  
Metabolic Reprogramming ◽  
Loss Of Function ◽  
Therapeutic Approaches ◽  
Gain Of Function ◽  
The Impact

Frequent p53 mutations (mutp53) not only abolish tumor suppressor capacities but confer various gain-of-function (GOF) activities that impacts molecules and pathways now regarded as central for tumor development and progression. Although the complete impact of GOF is still far from being fully understood, the effects on proliferation, migration, metabolic reprogramming, and immune evasion, among others, certainly constitute major driving forces for human tumors harboring them. In this review we discuss major molecular mechanisms driven by mutp53 GOF. We present novel mechanistic insights on their effects over key functional molecules and processes involved in cancer. We analyze new mechanistic insights impacting processes such as immune system evasion, metabolic reprogramming, and stemness. In particular, the increased lipogenic activity through the mevalonate pathway (MVA) and the alteration of metabolic homeostasis due to interactions between mutp53 and AMP-activated protein kinase (AMPK) and Sterol regulatory element-binding protein 1 (SREBP1) that impact anabolic pathways and favor metabolic reprograming. We address, in detail, the impact of mutp53 over metabolic reprogramming and the Warburg effect observed in cancer cells as a consequence, not only of loss-of-function of p53, but rather as an effect of GOF that is crucial for the imbalance between glycolysis and oxidative phosphorylation. Additionally, transcriptional activation of new targets, resulting from interaction of mutp53 with NF-kB, HIF-1α, or SREBP1, are presented and discussed. Finally, we discuss perspectives for targeting molecules and pathways involved in chemo-resistance of tumor cells resulting from mutp53 GOF. We discuss and stress the fact that the status of p53 currently constitutes one of the most relevant criteria to understand the role of autophagy as a survival mechanism in cancer, and propose new therapeutic approaches that could promote the reduction of GOF effects exercised by mutp53 in cancer.

scholarly journals Hericium erinaceusInhibits TNF-α-Induced Angiogenesis and ROS Generation through Suppression of MMP-9/NF-κB Signaling and Activation of Nrf2-Mediated Antioxidant Genes in Human EA.hy926 Endothelial Cells

2016 ◽  
Vol 2016 ◽  
pp. 1-15 ◽  
Author(s):  
Hebron C. Chang ◽  
Hsin-Ling Yang ◽  
Jih-Hao Pan ◽  
Mallikarjuna Korivi ◽  
Jian-You Pan ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Transcriptional Activation ◽  
Molecular Mechanisms ◽  
Nuclear Translocation ◽  
Intercellular Adhesion Molecule ◽  
Heme Oxygenase 1 ◽  
Related Factor ◽  
Dependent Manner ◽  
Antioxidant Genes ◽  
Anti Inflammatory

Hericium erinaceus(HE) is an edible mushroom that has been shown to exhibit anticancer and anti-inflammatory activities. We investigated the antiangiogenic and antioxidant potentials of ethanol extracts of HE in human endothelial (EA.hy926) cells upon tumor necrosis factor-α- (TNF-α-) stimulation (10 ng/mL). The underlying molecular mechanisms behind the pharmacological efficacies were elucidated. We found that noncytotoxic concentrations of HE (50–200 μg/mL) significantly inhibited TNF-α-induced migration/invasion and capillary-like tube formation of endothelial cells. HE treatment suppressed TNF-α-induced activity and/or overexpression of matrix metalloproteinase-9 (MMP-9) and intercellular adhesion molecule-1 (ICAM-1). Furthermore, HE downregulated TNF-α-induced nuclear translocation and transcriptional activation of nuclear factor-κB (NF-κB) followed by suppression of I-κB (inhibitor-κB) degradation. Data from fluorescence microscopy illustrated that increased intracellular ROS production upon TNF-α-stimulation was remarkably inhibited by HE pretreatment in a dose-dependent manner. Notably, HE triggered antioxidant gene expressions of heme oxygenase-1 (HO-1),γ-glutamylcysteine synthetase (γ-GCLC), and glutathione levels, which may contribute to inhibition of ROS. Increased antioxidant status was associated with upregulated nuclear translocation and transcriptional activation of NF-E2related factor-2 (Nrf2) in HE treated cells. Our findings conclude that antiangiogenic and anti-inflammatory activities ofH. erinaceusmay contribute to its anticancer property through modulation of MMP-9/NF-κB and Nrf2-antioxidant signaling pathways.

scholarly journals IL-33 Inhibits TNF-α-Induced Osteoclastogenesis and Bone Resorption

2020 ◽  
Vol 21 (3) ◽  
pp. 1130 ◽  
Author(s):  
Fumitoshi Ohori ◽  
Hideki Kitaura ◽  
Saika Ogawa ◽  
Wei-Ren Shen ◽  
Jiawei Qi ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Nuclear Translocation ◽  
Bone Marrow Cells ◽  
Bone Destruction ◽  
Osteoclast Formation ◽  
Tartrate Resistant Acid Phosphatase ◽  
Ct Reconstruction ◽  
Tnf Α

Interleukin (IL)-33 is a member of the IL-1 family, which acts as an alarmin. Several studies suggested that IL-33 inhibited osteoclastogenesis and bone resorption. Tumor necrosis factor-α (TNF-α) is considered a direct inducer of osteoclastogenesis. However, there has been no report regarding the effect of IL-33 on TNF-α-induced osteoclastogenesis and bone resorption. The objective of this study is to investigate the role of IL-33 on TNF-α-induced osteoclastogenesis and bone resorption. In an in vitro analysis of osteoclastogenesis, osteoclast precursors, which were derived from bone marrow cells, were treated with or without IL-33 in the presence of TNF-α. Tartrate-resistant acid phosphatase (TRAP) staining solution was used to assess osteoclast formation. In an in vivo analysis of mouse calvariae, TNF-α with or without IL-33 was subcutaneously administrated into the supracalvarial region of mice daily for 5 days. Histological sections were stained for TRAP, and osteoclast numbers were determined. Using micro-CT reconstruction images, the ratio of bone destruction area on the calvariae was evaluated. The number of TRAP-positive cells induced by TNF-α was significantly decreased with IL-33 in vitro and in vivo. Bone resorption was also reduced. IL-33 inhibited IκB phosphorylation and NF-κB nuclear translocation. These results suggest that IL-33 inhibited TNF-α-induced osteoclastogenesis and bone resorption.

scholarly journals OP0241 IL9 MODULATION OF OSTEOCLASTS DIFFERENTIATION AND IMPACTS ON BONE METABOLISM

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 152.1-152
Author(s):  
M. Saad ◽  
S. Rauber ◽  
G. Schett ◽  
A. Ramming
Keyword(s):  
Rheumatoid Arthritis ◽  
Bone Metabolism ◽  
Mouse Models ◽  
Intracellular Signaling ◽  
Bone Matrix ◽  
Osteoclast Differentiation ◽  
Bone Destruction ◽  
Microcomputed Tomography ◽  
Tartrate Resistant Acid Phosphatase ◽  
Resolution Of Inflammation

Background:Osteoclasts are multinucleated cells originating from the monocytes/macrophage lineage and require receptor activator of NF-κB ligand (RANK-L) and macrophage-colony-stimulating factor (M-CSF) for their development. They play a major role in bone remodeling by degrading the calcified bone matrix. They are considered as one of the culprits in bone destruction in many inflammatory diseases e.g. rheumatoid arthritis and osteoporosis. In previous work by our group, it was observed that IL-9 mediated the resolution of inflammation in rheumatoid arthritis and hence protected against bone degradation in animal models. Despite this protection was particularly associated to the resolution of inflammation, our data also supported the hypothesis of a direct signalling of IL-9 to osteoclasts.Objectives:The aim of this study was to investigate the modulating effect of IL-9 on osteoclasts and on the bone metabolism.Methods:Osteoclasts differentiation was studied in the mouse models of antigen induced arthritis (AIA) and KBxN serum induced arthritis (SIA) in the presence and absence of IL-9 by histomorphometric analysis and microcomputed tomography scans (µCT). Osteoclasts were generated from bone marrow derived monocytes of BALB/c mice with M-CSF, RANKL and IL-9, which were added in varying concentrations to induce osteoclast differentiation. Tartrate-resistant acid phosphatase (TRAP) staining was performed to follow the differentiation steps from monocytes into multinucleated osteoclasts and to determine the effects of IL-9 on osteoclastogenesis. Additionally, we performed RNA-seq and seahorse analysis to detect IL-9 dependent, differentially expressed genes and metabolites. Intracellular signaling as induced by IL9R activation was followed by western blot analysis.Results:IL-9 KO mice showed higher numbers of osteoclasts as compared to wild-type mice in the mouse models of AIA and SIA. Microcomputed tomography showed pronounced loss of the trabecular network and bone volume as signs of inflammation-induced osteopenia in Il9−/− mice. We found that osteoclasts express high levels of IL-9R. Next, monocytes were differentiated into osteoclasts in the presence of different concentrations of recombinant IL-9. Cells cultured in the presence of IL-9 showed significantly impaired differentiation into osteoclasts. We observed phosphorylation of STAT3 and STAT5 in cultured osteoclasts in dependency of IL-9. Furthermore, the presence of IL-9 during osteoclast differentiation impacted the gene expression levels of characteristic osteoclast related genes such as NFATc1, Cathepsin K and TRAP. Furthermore, IL-9 showed a major impact on mitochondrial respiration rate and glycolysis as assessed by Seahorse assays.Conclusion:IL-9 exerted direct effects on osteoclast differentiation and modulated the expression of several genes that are related to osteoclast differentiation and function.Disclosure of Interests:mina saad: None declared, Simon Rauber: None declared, Georg Schett Speakers bureau: AbbVie, BMS, Celgene, Janssen, Eli Lilly, Novartis, Roche and UCB, Andreas Ramming Grant/research support from: Pfizer, Novartis, Consultant of: Boehringer Ingelheim, Novartis, Gilead, Pfizer, Speakers bureau: Boehringer Ingelheim, Roche, Janssen

Toll-like receptor 7 regulates osteoclastogenesis in rheumatoid arthritis

2019 ◽  
Vol 166 (3) ◽  
pp. 259-270 ◽  
Author(s):  
Kyoung-Woon Kim ◽  
Bo-Mi Kim ◽  
Ji-Yeon Won ◽  
Kyung-Ann Lee ◽  
Hae-Rim Kim ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Osteoclast Differentiation ◽  
Bone Destruction ◽  
Synovial Fibroblasts ◽  
Enzyme Linked Immunosorbent Assay ◽  
Signal Molecules ◽  
Signal Pathways ◽  
Tartrate Resistant Acid Phosphatase ◽  
Toll Like Receptor ◽  
Multinucleated Cells

Abstract This study aimed to determine the regulatory role of toll-like receptor 7 (TLR7) in receptor activator of nuclear factor kappa-B ligand (RANKL) production and osteoclast differentiation in rheumatoid arthritis (RA). In confocal microscopy, the co-expression of TLR7, CD55 and RANKL was determined in RA synovial fibroblasts. After RA synovial fibroblasts were treated with imiquimod, the RANKL gene expression and protein production were determined by real-time polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA). Osteoclastogenesis from peripheral blood CD14+ monocytes which were cultured with imiquimod was assessed by determining the numbers of tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cells. The signal pathways mediating the TLR7-induced RANKL expression and osteoclastogenesis were analysed after inhibition of intracellular signal molecules and their phosphorylation. Imiquimod stimulated the expression of TLR7 and RANKL and production of RANKL in RA synovial fibroblasts, increasing the phosphorylation of TRAF6, IRF7, mitogen-activated protein kinases (MAPK), c-Jun and NFATc1. When CD14+ monocytes were cultured with imiquimod or co-cultured with imiquimod-pre-treated RA synovial fibroblasts, they were differentiated into TRAP+ multinucleated osteoclasts in the absence of RANKL. TLR7 activation-induced osteoclastogenesis in RA through direct induction of osteoclast differentiation from its precursors and up-regulation of RANKL production in RA synovial fibroblasts. Thus, the blockage of TLR7 pathway could be a promising therapeutic strategy for preventing bone destruction in RA.

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