Biphasic regulation of chondrocytes by Rela through induction of anti-apoptotic and catabolic target genes

Kobayashi, Hiroshi; Chang, Song Ho; Mori, Daisuke; Itoh, Shozo; Hirata, Makoto; Hosaka, Yoko; Taniguchi, Yuki; Okada, Kinya; Mori, Yoshifumi; Yano, Fumiko; Chung, Ung‐il; Akiyama, Haruhiko; Kawaguchi, Hiroshi; Tanaka, Sakae; Saito, Taku

doi:10.1038/ncomms13336

Cited by 88 publications

(91 citation statements)

References 46 publications

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“…Rela is the key subunit of the NF-ĸB family [31]. Rela/p65 plays an essential role in the process of mediating NF-κB signaling and is involved in chondrogenic differentiation, cell survival and catabolic enzyme production [31]. Tumor necrosis factor receptor-associated factor 3 (Traf3) can activate NF-κB through both canonical and non-canonical signaling pathways [32,33].…”

Section: Discussionmentioning

confidence: 99%

“…The NF-κB family of transcription factors plays important roles in a wide range of biological processes such as inflammation, immune responses, cell proliferation, cell differentiation, cell survival and apoptosis [30,31]. Rela is the key subunit of the NF-ĸB family [31]. Rela/p65 plays an essential role in the process of mediating NF-κB signaling and is involved in chondrogenic differentiation, cell survival and catabolic enzyme production [31].…”

Section: Discussionmentioning

confidence: 99%

“…The NF-ĸB family of transcription factors contains five members, p50, p52, p65 (Rela), Relb and c-Rel [28,29]. The NF-κB family of transcription factors plays important roles in a wide range of biological processes such as inflammation, immune responses, cell proliferation, cell differentiation, cell survival and apoptosis [30,31]. Rela is the key subunit of the NF-ĸB family [31].…”

Section: Discussionmentioning

confidence: 99%

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miR-155-5p is Negatively Associated with Acute Pancreatitis and Inversely Regulates Pancreatic Acinar Cell Progression by Targeting Rela and Traf3

Liu¹,

Zou²,

Wang³

et al. 2018

Cell Physiol Biochem

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Background/Aims: Acute pancreatitis contributes to high mortality in pancreatitis patients, and miRNAs play a vital role in the development of acute pancreatitis (AP), however, its precise biological role remains largely elusive. Methods: To clarify the potential mechanisms of miRNAs in AP, we built mouse models of mild acute pancreatitis (MAP) and moderate/ severe acute pancreatitis (SAP). MiRNA microarray analysis and Real-time quantitative PCR (qRT-PCR) were used to analyze the expression of miRNA in MAP/SAP. TargetScan software, dual-luciferase gene reporter assays and Western blotting were used to assess the target genes of miR-155-5p in AP. Results: miR-155-5p was significantly decreased in MAP/SAP mice compared to controls. In pancreatic acinar AR42J cells transfected with miR-155-5p mimic, the expression of Rela and Traf3 notably decreased in both the caerulein- and TLC-S-induced groups compared with the negative control (NC); however, the expression of Rela and Traf3 notably increased after transfection with miR-155-5p inhibitor. Combined analysis using the TargetScan software and dual-luciferase gene reporter assays indicated that Rela and Traf3 were both targeted by miR-155-5p. Meanwhile, the expression of Ptgs2 also decreased after transfection of the AR42J cells with miR-155-5p mimic. The opposite results were found when miR-155-5p inhibitor was transfected into the AR42J cells. In addition, we treated caerulein- and TLC-S-induced AR42J cells with the Rela inhibitor helenalin and found that the expression of Rela, Traf3 and Ptgs2 decreased compared with the NC, while the expression of miR-155-5p did not show any significant difference. Furthermore, we found that miR-155-5p was significantly down-regulated in pancreatitis patients. Conclusion: miR-155-5p inversely regulated AP development through the Rela/Traf3/Ptgs2 signaling pathway.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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miR-155-5p is Negatively Associated with Acute Pancreatitis and Inversely Regulates Pancreatic Acinar Cell Progression by Targeting Rela and Traf3

Liu¹,

Zou²,

Wang³

et al. 2018

Cell Physiol Biochem

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“…Each zone contains chondrocytes at different stages of differentiation. For example, p65 expression is observed throughout the growth plate, but mainly in the resting and hypertrophic zones, suggesting that the classical NF-κB pathway is involved in normal bone development, particularly endochondral ossification [7,10]. Overexpression of a dominant negative form of IκBα that blocks NF-κB activation leads to abnormal limb bud development and downregulation of BMP signaling in chicken embryos [15].…”

Section: The Role Of the Classical Nf-κb Pathway In Chondrogenic Devementioning

confidence: 99%

“…The transcription factor nuclear factor-κB (NF-κB) regulates the expression of a wide variety of genes involved in immune and inflammatory responses, cell proliferation, tumorigenesis, cell survival, and development [5,6]. Several studies have reported that the NF-κB transcription family is involved in endochondral ossification and limb outgrowth under physiological conditions [7][8][9][10].…”

Section: Introductionmentioning

confidence: 99%

NF-κB Signaling Regulates Physiological and Pathological Chondrogenesis

Jimi

Huang

Nakatomi

2019

IJMS

221

124

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The nuclear factor-κB (NF-κB) is a transcription factor that regulates the expression of genes that control cell proliferation and apoptosis, as well as genes that respond to inflammation and immune responses. There are two means of NF-κB activation: the classical pathway, which involves the degradation of the inhibitor of κBα (IκBα), and the alternative pathway, which involves the NF-κB-inducing kinase (NIK, also known as MAP3K14). The mouse growth plate consists of the resting zone, proliferative zone, prehypertrophic zone, and hypertrophic zone. The p65 (RelA), which plays a central role in the classical pathway, is expressed throughout the cartilage layer, from the resting zone to the hypertrophic zone. Inhibiting the classical NF-κB signaling pathway blocks growth hormone (GH) or insulin-like growth factor (IGF-1) signaling, suppresses cell proliferation, and suppresses bone morphogenetic protein 2 (BMP2) expression, thereby promoting apoptosis. Since the production of autoantibodies and inflammatory cytokines, such as tumor necrosis factor-α (TNFα), interleukin (IL)-1β, IL-6, and IL-17, are regulated by the classical pathways and are increased in rheumatoid arthritis (RA), NF-κB inhibitors are used to suppress inflammation and joint destruction in RA models. In osteoarthritis (OA) models, the strength of NF-κB-activation is found to regulate the facilitation or suppression of OA. On the other hand, RelB is involved in the alternative pathway, and is expressed in the periarticular zone during the embryonic period of development. The alternative pathway is involved in the generation of chondrocytes in the proliferative zone during physiological conditions, and in the development of RA and OA during pathological conditions. Thus, NF-κB is an important molecule that controls normal development and the pathological destruction of cartilage.

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RelA promotes proliferation but inhibits osteogenic and chondrogenic differentiation of mesenchymal stem cells

et al. 2020

FEBS Letters

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NF‐κB is known to be implicated in skeletal development and related diseases. Previous studies have shown that RelA, a key subunit of NF‐κB, is involved in osteoblast and chondrocyte survival and differentiation. Yet, the physiological roles of RelA in mesenchymal stem cells (MSCs), which give rise to both chondrocytes and osteoblasts, are still poorly understood. Here, we generated Prrx1‐Cre;RelAf/f mice to delete RelA in Prrx1+ bone marrow MSCs and found that RelA deletion led to decreased MSC proliferation and altered differentiation, with increased osteogenic and chondrogenic differentiation but decreased adipogenic differentiation. Bone size and mass were not significantly changed in the mutant mice, although they developed moderate osteoarthritis‐like phenotypes. Thus, our studies reveal important but discordant functions of RelA in MSC proliferation and differentiation, and provide an explanation why MSC‐specific RelA knockout mice only develop minor skeletal phenotypes.

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Biphasic regulation of chondrocytes by Rela through induction of anti-apoptotic and catabolic target genes

Cited by 88 publications

References 46 publications

miR-155-5p is Negatively Associated with Acute Pancreatitis and Inversely Regulates Pancreatic Acinar Cell Progression by Targeting Rela and Traf3

miR-155-5p is Negatively Associated with Acute Pancreatitis and Inversely Regulates Pancreatic Acinar Cell Progression by Targeting Rela and Traf3

NF-κB Signaling Regulates Physiological and Pathological Chondrogenesis

RelA promotes proliferation but inhibits osteogenic and chondrogenic differentiation of mesenchymal stem cells

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