Nuclear factor E2 p45-related factor 2 negatively regulates chondrogenesis

Hinoi, Eiichi; Takarada, Takeshi; Fujimori, Sayumi; Wang, Liyang; Iemata, Mika; Uno, Kyosuke; Yoneda, Yukio

doi:10.1016/j.bone.2006.08.016

Cited by 61 publications

(44 citation statements)

References 23 publications

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“…In direct contrast, it has been reported that increased expression of Nrf2 in a subset of rheumatoid arthritis patients could lead to a more severe disease state (46). In addition, Nrf2 may play complex roles in articular cells as this transcription factor mediates the expression of antioxidant genes but negatively regulates chondrocyte and osteoblast differentiation (14,15). Therefore, the role of Nrf2 in arthritis remains unclear.…”

Section: Innovationmentioning

confidence: 80%

Deficiency of Nrf2 Accelerates the Effector Phase of Arthritis and Aggravates Joint Disease

Maicas

Ferrándiz

Brines

et al. 2011

Antioxidants & Redox Signaling

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Aims: Although oxidative stress participates in the etiopathogenesis of rheumatoid arthritis, its importance in this inflammatory disease has not been fully elucidated. In this study, we analyzed the relevance of the transcription factor Nrf2, master regulator of redox homeostasis, in the effector phase of an animal model of rheumatoid arthritis, using the transfer of serum from K/BxN transgenic mice to Nrf2 -/-mice. Results: Nrf2 deficiency accelerated the incidence of arthritis, and animals showed a widespread disease affecting both front and hind paws. Therefore, the inflammatory response was enhanced, with increased migration of leukocytes and joint destruction in front paws. We observed an increased production of tumor necrosis factor-a, interleukin-6, and CXCL-1 in the joint, with small changes in eicosanoid levels. Serum levels of CXCL-1 and receptor activator for nuclear factor jB ligand were enhanced and osteocalcin decreased in arthritic Nrf2 -/-mice. The expression of cyclooxygenase-2, inducible nitric oxide synthase, and peroxynitrite in the joints was higher in Nrf2 deficiency, whereas heme oxygenase-1 was downregulated. Innovation: Nrf2 may be a therapeutic target for arthritis. Conclusion: Our results support a protective role of Nrf2 against joint inflammation and degeneration in arthritis. Antioxid. Redox Signal. 15, 889-901.

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Section: Innovationmentioning

confidence: 80%

Deficiency of Nrf2 Accelerates the Effector Phase of Arthritis and Aggravates Joint Disease

Maicas

Ferrándiz

Brines

et al. 2011

Antioxidants & Redox Signaling

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“…Hydrogen peroxide formation induced by FasL was prevented in the presence of pyruvate ( Fig. 2A, upper panels), which acts as a potent intracellular scavenger for H 2 O 2 (37)(38)(39). Superoxide anion formation was drastically reduced by the cell permeable manganic-porphyrins MnTE-2-PyP (Fig.…”

Section: Fasl-induced Gsh Loss Is Independent Of But Necessary For mentioning

confidence: 96%

Glutathione Depletion Is Necessary for Apoptosis in Lymphoid Cells Independent of Reactive Oxygen Species Formation

Franco

Panayiotidis²,

Cidlowski

2007

Journal of Biological Chemistry

240

193

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Changes in the intracellular redox environment of cells have been reported to be critical for the activation of apoptotic enzymes and the progression of programmed cell death. Glutathione (GSH) depletion is an early hallmark observed in apoptosis, and we have demonstrated that GSH efflux during death receptor-mediated apoptosis occurs via a GSH transporter. We now evaluate the relationship between GSH depletion, the generation of reactive oxygen species (ROS), and the progression of apoptosis. Simultaneous single cell analysis of changes in GSH content and ROS formation by multiparametric FACS revealed that loss of intracellular GSH was paralleled by the generation of different ROS including hydrogen peroxide, superoxide anion, hydroxyl radical, and lipid peroxides. However, inhibition of ROS formation by a variety of antioxidants showed that GSH loss was independent from the generation of ROS. Furthermore, GSH depletion was observed to be necessary for ROS generation. Interestingly, high extracellular thiol concentration (GSH and N-acetyl-cysteine) inhibited apoptosis, whereas, inhibition of ROS generation by other non-thiol antioxidants was ineffective in preventing cell death. Finally, GSH depletion was shown to be a necessary for the progression of apoptosis activated by both extrinsic and intrinsic signaling pathways. These results document a necessary and critical role for GSH loss in apoptosis and clearly uncouple for the first time GSH depletion from ROS formation.Apoptosis or programmed cell death is a ubiquitous, evolutionary conserved process. Under physiological conditions it is important not only in the turnover of cells in all tissues, but also during the normal development and senescence of the organism. Moreover, its deregulation has been observed to occur as either a cause or consequence of distinct pathologies (1, 2). For example, apoptosis mediated by Fas ligand (FasL) 3 receptor (Fas/CD95/Apo-1) activation is necessary for the immune system homeostasis because of its role in the rapid clearance of immunoreactive T cells maintaining the immune balance and reducing the risk of autoimmune diseases (3). Apoptosis is a highly organized process characterized by the progressive activation of precise pathways leading to specific biochemical and morphological alterations. Initial stages of apoptosis are characterized by reactive oxygen species (ROS) formation, changes in intracellular ionic homeostasis, cell shrinkage, loss of membrane lipid asymmetry, and chromatin condensation. Later stages associated with the execution phase of apoptosis are characterized by activation of execution caspases and endonucleases, apoptotic body formation, and cell fragmentation (1, 4, 5). Apoptosis has been widely reported to be modulated by changes in the redox status of the cell; however, the precise mechanisms involved are still unclear (6, 7). Reduced glutathione (GSH) is the most abundant low molecular weight thiol in animal cells and is involved in many cellular processes including antioxidant defense, drug det...

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“…This crosstalk can probably influence the adaptive defenses of the stem cells and be important for the maintenance of homeostasis of the niche. In addition to hepato-cholagionenesis in adult liver [47,84,85], the airways basal stem cell system for proliferating or self-renewal in the lung [43], enterogenesis in the intestinal crypt [86], adult neurogenesis occurring in the subventricular zone and/or the dentate gyrus of the hippocampus in the central nervous system [15,87,88], dermatogenesis in the skin [17,89,90], osteogenesis in bone [91,92], cell fate determination in hematopoiesis [93,94] and angiogenesis in various tissues [95] might all be valuable settings for further evaluation ( Figure 5A). …”

Section: Lessons From Genetically Engineered Mice Biological Significmentioning

confidence: 99%

CROSSTALK BETWEEN Nrf2 AND NOTCH SIGNALING

Wakabayashi

2014

Free Radical Biology and Medicine

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The transcription factor, Nrf2 (nuclear factor, erythroid derived 2, like 2) belongs to the CNC-bZip protein family, forming a transcriptosome with its direct heterodimer partner, sMaf, and co-factors such as CBP/p300. Nrf2 binds to one or more ARE (Antioxidant Response Element) that are located in the gene regulatory regions of the hundreds of Nrf2 target genes. The ARE is a key enhancer that is activated in response to endogenous or exogenous stresses in order to maintain cellular and tissue homeostasis. Data emanating from gene expression microarray analyses comparing Nrf2-disrupted and wild-type mouse embryonic fibroblasts (MEF) showed that expression of Notch1 and Notch-signaling related genes were decreased in Nrf2-disrupted cells. This observation triggered our research on Nrf2-Notch crosstalk. A functional ARE has been identified upstream of the Notch1 major transcription start site. Furthermore, an Rbpjκ binding site is conserved on the promoters of Nrf2 among animal species. Notch1 is one of the transmembrane Notch family receptors, which drives Notch-signaling together with the Rbpjκ transcription factor. After canonically accepting ligands such as Jags and Deltas, the receptor undergoes cleavage to yield the Notch intracellular domain which translocates to the nucleus. Recent studies using conditional knockout mice indicate that Notch1 as well as Notch2 play important roles postnatally in liver development and in maintenance of hepatic function. In this review, we summarize current understanding of the role of reciprocal transcriptional regulation between Nrf2 and Notch in adult liver from studies using Nrf2, Keap1, and Notch1 genetically engineered mice.

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Nuclear factor E2 p45-related factor 2 negatively regulates chondrogenesis

Cited by 61 publications

References 23 publications

Deficiency of Nrf2 Accelerates the Effector Phase of Arthritis and Aggravates Joint Disease

Deficiency of Nrf2 Accelerates the Effector Phase of Arthritis and Aggravates Joint Disease

Glutathione Depletion Is Necessary for Apoptosis in Lymphoid Cells Independent of Reactive Oxygen Species Formation

CROSSTALK BETWEEN Nrf2 AND NOTCH SIGNALING

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