RANKL induces Bach1 nuclear import and attenuates Nrf2‐mediated antioxidant enzymes, thereby augmenting intracellular reactive oxygen species signaling and osteoclastogenesis in mice

Kanzaki, Hiroyuki; Shinohara, Fumiaki; Itohiya, Kanako; Yamaguchi, Yuuki; Katsumata, Yuta; Matsuzawa, Masazumi; Fukaya, Sari; Miyamoto, Yutaka; Wada, Satoshi; Nakamura, Yoshiki

doi:10.1096/fj.201600826r

Cited by 56 publications

(57 citation statements)

References 41 publications

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“…Indeed, RANKL stimulation decreases expression of NRF2-dependent cytoprotective enzymes, thereby facilitating intracellular ROS signaling (Kanzaki et al, 2013, 2016b). Induction of cytoprotective enzymes by NRF2 activation subsequently inhibits osteoclastogenesis (Kanzaki et al, 2013, 2014, 2015; Sakai et al, 2013; Gambari et al, 2014; Lee et al, 2014; Lu et al, 2015; Bhattarai et al, 2016).…”

Section: Mechanisms That Protect Against Oxidative Stressmentioning

confidence: 99%

Pathways that Regulate ROS Scavenging Enzymes, and Their Role in Defense Against Tissue Destruction in Periodontitis

et al. 2017

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Periodontitis, an inflammatory disease that affects the tissues surrounding the teeth, is a common disease worldwide. It is caused by a dysregulation of the host inflammatory response to bacterial infection, which leads to soft and hard tissue destruction. In particular, it is the excessive inflammation in response to bacterial plaque that leads to the release of reactive oxygen species (ROS) from neutrophils, which, then play a critical role in the destruction of periodontal tissue. Generally, ROS produced from immune cells exhibit an anti-bacterial effect and play a role in host defense and immune regulation. Excessive ROS, however, can exert cytotoxic effects, cause oxidative damage to proteins, and DNA, can interfere with cell growth and cell cycle progression, and induce apoptosis of gingival fibroblasts. Collectively, these effects enable ROS to directly induce periodontal tissue damage. Some ROS also act as intracellular signaling molecules during osteoclastogenesis, and can thus also play an indirect role in bone destruction. Cells have several protective mechanisms to manage such oxidative stress, most of which involve production of cytoprotective enzymes that scavenge ROS. These enzymes are transcriptionally regulated via NRF2, Sirtuin, and FOXO. Some reports indicate an association between periodontitis and these cytoprotective enzymes' regulatory axes, with superoxide dismutase (SOD) the most extensively investigated. In this review article, we discuss the role of oxidative stress in the tissue destruction manifest in periodontitis, and the mechanisms that protect against this oxidative stress.

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Section: Mechanisms That Protect Against Oxidative Stressmentioning

confidence: 99%

Pathways that Regulate ROS Scavenging Enzymes, and Their Role in Defense Against Tissue Destruction in Periodontitis

et al. 2017

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“…In response to oxidative stress, Keap1‐interactors displace Nrf2, which then migrates into the nucleus and binds the antioxidant response element (ARE) in the promoter of its target genes, as a heterodimer with small Maf proteins . Another transcription factor (BTB and CNC homology 1, Bach1) is involved in transcriptional regulation as a Nrf2 competitor and is shuttled in and out of the nucleus to respectively attenuate or liberate Nrf2 activity in response to different stimuli . Reduced Nrf2 activity has been linked to a number of pathological conditions .…”

Section: Introductionmentioning

confidence: 99%

“…(10) Another transcription factor (BTB and CNC homology 1, Bach1) is involved in transcriptional regulation as a Nrf2 competitor and is shuttled in and out of the nucleus to respectively attenuate or liberate Nrf2 activity in response to different stimuli. (11,12) Reduced Nrf2 activity has been linked to a number of pathological conditions. (13)(14)(15)(16)(17)(18) Furthermore, alterations of the Keap1/Nrf2 pathway have been reported in animal models of bone disease, and lack of Nrf2 exacerbated pathological phenotypes.…”

Section: Introductionmentioning

confidence: 99%

Absence of Dipeptidyl Peptidase 3 Increases Oxidative Stress and Causes Bone Loss

Menale

Robinson

Palagano

et al. 2019

Journal of Bone and Mineral Research

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Controlling oxidative stress through the activation of antioxidant pathways is crucial in bone homeostasis, and impairments of the cellular defense systems involved contribute to the pathogenesis of common skeletal diseases. In this work we focused on the dipeptidyl peptidase 3 (DPP3), a poorly investigated ubiquitous zinc‐dependent exopeptidase activating the Keap1‐Nrf2 antioxidant pathway. We showed Dpp3 expression in bone and, to understand its role in this compartment, we generated a Dpp3 knockout (KO) mouse model and specifically investigated the skeletal phenotype. Adult Dpp3 KO mice showed a mild growth defect, a significant increase in bone marrow cellularity, and bone loss mainly caused by increased osteoclast activity. Overall, in the mouse model, lack of DPP3 resulted in sustained oxidative stress and in alterations of bone microenvironment favoring the osteoclast compared to the osteoblast lineage. Accordingly, in vitro studies revealed that Dpp3 KO osteoclasts had an inherent increased resorptive activity and ROS production, which on the other hand made them prone to apoptosis. Moreover, absence of DPP3 augmented bone loss after estrogen withdrawal in female mice, further supporting its relevance in the framework of bone pathophysiology. Overall, we show a nonredundant role for DPP3 in the maintenance of bone homeostasis and propose that DPP3 might represent a possible new osteoimmunological player and a marker of human bone loss pathology. © 2019 American Society for Bone and Mineral Research.

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“…Previously, we reported that Nrf2 was transiently down‐regulated during osteoclastogenesis . In these studies, we also found that overexpression of Nrf2 inhibited osteoclastogenesis, and knockdown of Nrf2 induced osteoclastogenesis.…”

Section: Introductionmentioning

confidence: 62%

Dimethyl fumarate inhibits osteoclasts via attenuation of reactive oxygen species signalling by augmented antioxidation

Yamaguchi

Kanzaki

Katsumata

et al. 2017

J Cellular Molecular Medi

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Bone destructive diseases are common worldwide and are caused by dysregulation of osteoclast formation and activation. During osteoclastogenesis, reactive oxygen species (ROS) play a role in the intracellular signalling triggered by receptor activator of nuclear factor-jB ligand (RANKL) stimulation. Previously, we demonstrated that induction of antioxidant enzymes by Nrf2 activation using Nrf2-gene transfer, an ETGEpeptide or polyphenols, successfully ameliorated RANKL-dependent osteoclastogenesis. Dimethyl fumarate (DMF) has been shown to activate Nrf2 signalling and has been lately used in clinical trials for neurodegenerative diseases. In this study, we hypothesized that Nrf2 activation by DMF would inhibit osteoclastogenesis and bone destruction via attenuation of intracellular ROS signalling through antioxidant mechanisms. RAW 264.7 cells were used as osteoclast progenitor cells. We found that DMF induced Nrf2 translocation to the nucleus, augmented Nrf2 promoter-luciferase reporter activity and increased antioxidant enzyme expression. Using flow cytometry, we found that DMF attenuated RANKL-mediated intracellular ROS generation, which resulted in the inhibition of RANKL-mediated osteoclastogenesis. Local DMF injection into the calvaria of male BALB/c mice resulted in attenuated bone destruction in lipopolysaccharide-treated mice. In conclusion, we demonstrated in a preclinical setting that DMF inhibited RANKL-mediated osteoclastogenesis and bone destruction via induction of Nrf2-mediated transcription of antioxidant genes and consequent decrease in intracellular ROS levels. Our results suggest that DMF may be a promising inhibitor of bone destruction in diseases like periodontitis, rheumatoid arthritis and osteoporosis.Keywords: osteoclast Nrf2 dimethyl fumarate receptor activator of nuclear factor-kB ligand oxidative stress reactive oxygen species antioxidant response HO-1

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RANKL induces Bach1 nuclear import and attenuates Nrf2‐mediated antioxidant enzymes, thereby augmenting intracellular reactive oxygen species signaling and osteoclastogenesis in mice

Cited by 56 publications

References 41 publications

Pathways that Regulate ROS Scavenging Enzymes, and Their Role in Defense Against Tissue Destruction in Periodontitis

Pathways that Regulate ROS Scavenging Enzymes, and Their Role in Defense Against Tissue Destruction in Periodontitis

Absence of Dipeptidyl Peptidase 3 Increases Oxidative Stress and Causes Bone Loss

Dimethyl fumarate inhibits osteoclasts via attenuation of reactive oxygen species signalling by augmented antioxidation

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