Synovial cell death is regulated by TNF-α-induced expression of B-cell activating factor through an ERK-dependent increase in hypoxia-inducible factor-1α

Lee, Jae‐Wook; Lee, Ji-Young; Um, Sung Hee; Moon, Eun‐Yi

doi:10.1038/cddis.2017.26

Cited by 28 publications

(25 citation statements)

References 47 publications

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“…4 C ). On the other hand, by using primary chondrocytes from Col2a1‐CreER T2 ; Ezh2 f/f mice, we confirmed the decrease of Tnfsf13b in Ezh2 knockout chondrocytes (Fig. D , Supplementary Fig.…”

Section: Resultssupporting

confidence: 56%

Ezh2 Ameliorates Osteoarthritis by Activating TNFSF13B

Chen

Zhang

et al. 2020

Journal of Bone and Mineral Research

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Epigenetic regulation is highly correlated with osteoarthritis (OA) development, whereas its role and detailed mechanisms remain elusive. In this study, we explored the expression of EZH2, an H3K27me3 transferase, in human OA cartilages and its roles in regulating OA pathogenesis. Here, we found EZH2 was highly expressed in both mice and human OA cartilage samples by using histological analysis and RNA sequencing (RNA-Seq). The medial meniscectomy (MMx) OA model results indicated the conditional knockout of Ezh2 deteriorated OA pathological conditions. Furthermore, we showed the positive role of Ezh2 in cartilage wound healing and inhibition of hypertrophy through activating TNFSF13B, a member of the tumor necrosis factor superfamily. Further, we also indicated that the effect of TNFSF13B, increased by Ezh2, might boost the healing of chondrocytes through increasing the phosphorylation of Akt. Taken together, our results uncovered an EZH2-positive subpopulation existed in OA patients, and that EZH2-TNFSF13B signaling was responsible for regulating chondrocyte healing and hypertrophy. Thus, EZH2 might act as a new potential target for OA diagnosis and treatment. n 956 DU ET AL. 23. Ohata J, Zvaifler NJ, Nishio M, et al. Fibroblast-like synoviocytes of mesenchymal origin express functional B cell-activating factor of the TNF family in response to proinflammatory cytokines. J Immunol. 2005;174(2):864-70. 24. Bradley EW, Carpio LR, Westendorf JJ. Histone deacetylase 3 suppression increases PH domain and leucine-rich repeat phosphatase (Phlpp)1 expression in chondrocytes to suppress Akt signaling and matrix secretion. J Biol Chem. 2013;288:9572-82. 25. Zhang S, Chuah SJ, Lai RC, JHP H, Lim SK, Toh WS. MSC exosomes mediate cartilage repair by enhancing proliferation, attenuating apoptosis and modulating immune reactivity. Biomaterials. 2018;156: 16-27. Journal of Bone and Mineral Research n 964 DU ET AL.

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Section: Resultssupporting

confidence: 56%

Ezh2 Ameliorates Osteoarthritis by Activating TNFSF13B

Chen

Zhang

et al. 2020

Journal of Bone and Mineral Research

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“…BAFF expression is regulated by various signaling pathways, including the activation of JAK/STAT ( Woo et al ., 2013 ), CREB-binding protein/p300 ( Moon and Park, 2007 ), lipopolysaccharide (LPS)-induced protein kinase A-mediated CREB, Epac1-mediated Rap1 ( Moon et al ., 2011a , 2011b), nuclear factor-kappa B by LPS-induced production of reactive oxygen species (ROS) ( Moon et al ., 2006 ), and ROS-dependent protein kinase C (PKC)/c-Fos pathways. ERK pathways are also involved in TNF-α-induced BAFF expression in FLS ( Lee et al ., 2017 ). Our data show that BAFF expression by TNF-α could be associated with the activation of kinase (JNK, p38 and ERK) and transcription factors (p65, CREB, c-Fos and SP1) in FLS.…”

Section: Discussionmentioning

confidence: 99%

“…TNF-α-stimulated FLS express B-cell activating factor (BAFF), originally known as a B-cell proliferation and survival factor ( Mackay and Kalled, 2002 ; Lee et al ., 2017 ). BAFF is produced by immune cells (monocytes, dendritic cells, and macrophages) ( Mackay and Browning, 2002 ), and also by non-immune cells, such as salivary gland epithelial cells ( Ittah et al ., 2008 ), prostate epithelium ( Di Carlo et al ., 2009 ), and FLS ( Ohata et al ., 2005 ; Lee et al ., 2017 ). Excess levels of BAFF are detected in patients with an autoimmune disease, and particularly in the synovial tissue of patients with RA ( Nakajima et al ., 2007 ).…”

Section: Introductionmentioning

confidence: 99%

Synovial Cell Migration is Associated with B Cell Activating Factor Expression Increased by TNFα or Decreased by KR33426

Lee

Yoon

Thuy

et al. 2020

Biomolecules & Therapeutics

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Fibroblast-like synoviocytes (FLS) play a crucial role in initiating rheumatoid arthritis. B-cell activating factor (BAFF) plays a role in FLS survival as well as in B cell maturation and maintenance. Here, we investigated whether tumor necrosis factor (TNF)-α-induced BAFF expression controls FLS migration and whether BAFF expression in FLS could be regulated by KR33426 which is the inhibitor of BAFF binding to BAFF receptors (BAFF-R) by using MH7A synovial cells transfected with the SV40 T antigen. More TNF-α-treated cells migrated compared to the control. TNF-α increased BAFF expression in FLS, significantly. FLS migration was inhibited by the transfection with BAFF-siRNA. KR33426 also inhibited BAFF expression increased by TNF-α treatment in FLS as judged by western blotting, PCR, and transcriptional activity assay. Kinases including JNK, p38 and Erk were activated by TNF-α treatment. While JNK and p38 were inhibited by KR33426 treatment, no changes in Erk were observed. Transcription factors including p65, c-Fos, CREB and SP1 were enhanced by TNF-α treatment. Among them, c-Fos was inhibited by KR33426 treatment. Small interference(si)-RNA of c-fos decreased BAFF transcriptional activity. FLS migration induced by TNF-α was inhibited by the transfection with BAFF-siRNA. KR33426 increased Twist, Snail, Cadherin-11 and N-Cadherin. In contrast, KR33426 decreased E-cadherin and TNF-α-enhanced CCL2. Taken together, our results demonstrate that synovial cell migration via CCL2 expression could be regulated by BAFF expression which is decreased by KR33426 and c-Fos-siRNA. It suggests for the first time that the role of BAFF-siRNA on FLS migration might be matched in the effect of KR33426 on BAFF expression.

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“…An increasing amount of evidence demonstrates that hypoxia inducible factor-1α (HIF-1α) is the main upstream inducer of VEGFA, which plays a key role in tumor angiogenesis [ 36 , 37 ]. Recent studies have characterized a series of HIF-1α related pathways, such as the ERK [ 38 ], TNF-α [ 39 ], phosphatidylinositol-3-kinase (PI3K), mammalian homologue target of rapamycin (mTOR), and AKT [ 40 , 41 ] pathways. Here, we found that UBE2CP3 up-regulated the levels of p-ERK, phosphor-p70S6K (p-p70S6K), HIF-1α, and VEGFA in HCC cells.…”

Section: Discussionmentioning

confidence: 99%

Long non-coding RNA UBE2CP3 enhances HCC cell secretion of VEGFA and promotes angiogenesis by activating ERK1/2/HIF-1α/VEGFA signalling in hepatocellular carcinoma

Lin

Cao

Wang

et al. 2018

J Exp Clin Cancer Res

105

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BackgroundAngiogenesis is considered as an important process in the development of malignancies and is associated with cancer progression and metastasis. Hepatocellular carcinoma (HCC) is the most common primary tumor of the liver and is recognized as a typical angiogenic tumor. Thus, it is of great importance to study the underlying mechanism of angiogenesis in HCC. The long non-coding RNA (lncRNA) ubiquitin conjugating enzyme E2C pseudogene 3 (UBE2CP3) has been reported as an oncogene that promotes tumor metastasis in HCC. However, the role and underlying mechanisms of UBE2CP3 in HCC angiogenesis are still unclear.MethodsWe measured the expression levels of UBE2CP3 by in situ hybridization (ISH) and quantitative real-time polymerase chain reaction (qRT-PCR) in HCC patient samples. We also concomitantly used CD31/PAS double-staining to measure endothelial vessel (EV) density and used qRT-PCR to measure the CD31 mRNA level. HepG2 and SMMC-7721 cells were transfected with Lv-UBE2CP3 or Sh-UBE2CP3 virus to obtain stably over-expressing or knocking-down UBE2CP3 cell lines. The indirect effects of UBE2CP3 on ECs were studied by establishing a co-culture system using Transwell chambers with a 0.4-μm pore size. HCC cells and ECs in the co-culture system were separated, but the cytokines and growth factors were able to communicate with each other. Following exposed to HCC cells, ECs were collected for functional studies. Finally, we studied the function of UBE2CP3 in vivo by chick embryo chorioallantoic membrane (CAM) angiogenesis assays and nude mouse tumorigenicity assays.ResultsIn this study, we found that UBE2CP3 expression was higher in HCC tissues than in para-tumor tissues and was up-regulated in tissues with high EV density. Functionally, we found that in the co-culture systems, HCC cells overexpressing UBE2CP3 promoted HUVEC proliferation, migration and tube formation via the activation of ERK/HIF-1α/p70S6K/VEGFA signalling, increasing the level of VEGFA in HCC cell supernatant. In addition, the opposite results appeared when the expression of UBE2CP3 in HCC cells was knocked down. Consistent with these results, CAM angiogenesis assays and nude mouse tumorigenicity assays showed that UBE2CP3 expression up-regulated EV density in vivo.ConclusionOur study suggests that UBE2CP3 can enhance the interaction between HCC tumor cells and HUVECs and promote HCC tumorigenicity by facilitating angiogenesis.Electronic supplementary materialThe online version of this article (10.1186/s13046-018-0727-1) contains supplementary material, which is available to authorized users.

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Synovial cell death is regulated by TNF-α-induced expression of B-cell activating factor through an ERK-dependent increase in hypoxia-inducible factor-1α

Cited by 28 publications

References 47 publications

Ezh2 Ameliorates Osteoarthritis by Activating TNFSF13B

Ezh2 Ameliorates Osteoarthritis by Activating TNFSF13B

Synovial Cell Migration is Associated with B Cell Activating Factor Expression Increased by TNFα or Decreased by KR33426

Long non-coding RNA UBE2CP3 enhances HCC cell secretion of VEGFA and promotes angiogenesis by activating ERK1/2/HIF-1α/VEGFA signalling in hepatocellular carcinoma

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