Nuclear Nrf2 Induction by Protein Transduction Attenuates Osteoclastogenesis

Kanzaki, Hiroyuki; Shinohara, Fumiaki; Kajiya, Mikihito; Fukaya, Sari; Miyamoto, Yutaka; Nakamura, Yoshiki

doi:10.1016/j.freeradbiomed.2014.09.006

Cited by 38 publications

(46 citation statements)

References 37 publications

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“…To further confirm the effects of SFC and ALA on cell proliferation, RAW264.7 cells were plated on 24‐well plates and were cultured with various concentrations of SFC and ALA for 1 d. Whole‐cell protein lysate was prepared by using lysis buffer (18), and protein concentration was measured and calculated as protein content per well.…”

Section: Methodsmentioning

confidence: 99%

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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

et al. 2016

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Reactive oxygen species (ROS) play a role in intracellular signaling during osteoclastogenesis. We previously reported that transcriptional factor nuclear factor E2-related factor 2 (Nrf2) was exported from the nucleus to the cytoplasm by receptor activator of nuclear factor-κB ligand (RANKL), and that Nrf2 negatively regulated osteoclastogenesis via antioxidant enzyme up-regulation. Knockout mice of BTB and CNC homology 1 (Bach1)-the competitor for Nrf2 in transcriptional regulation-was known to attenuate RANKL-mediated osteoclastogenesis, although the mechanism remains unclear. Therefore, we hypothesized that RANKL could be involved in the nuclear translocation of Bach1, which would attenuate Nrf2-mediated antioxidant enzymes, thereby augmenting intracellular ROS signaling in osteoclasts. RANKL induced Bach1 nuclear import and Nrf2 nuclear export. Induction of Bach1 nuclear export increased Nrf2 nuclear import, augmented antioxidant enzyme expression, and, thus, diminished RANKL-mediated osteoclastogenesis via attenuated intracellular ROS signaling. Finally, an in vivo mouse bone destruction model clearly demonstrated that induction of Bach1 nuclear export inhibited bone destruction. In this study, we report that RANKL favors osteoclastogenesis via attenuation of Nrf2-mediated antioxidant enzyme expression by competing with Bach1 nuclear accumulation. Of importance, induction of Bach1 nuclear export activates Nrf2-dependent antioxidant enzyme expression, thereby attenuating osteoclastogenesis. Bach1 nuclear export might be a therapeutic target for such bone destructive diseases as rheumatoid arthritis, osteoporosis, and periodontitis.-Kanzaki, H., Shinohara, F., Itohiya, K., Yamaguchi, Y., Katsumata, Y., Matsuzawa, M., Fukaya, S., Miyamoto, Y., Wada, S., Nakamura, Y. RANKL induces Bach1 nuclear import and attenuates Nrf2-mediated antioxidant enzymes, thereby augmenting intracellular reactive oxygen species signaling and osteoclastogenesis in mice.

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Section: Methodsmentioning

confidence: 99%

“…Primary Abs for Nrf2, HO1, NQO1, histone H3, and β‐actin are described in Kanzaki et al . (18). Anti‐BACH1 Ab was purchased from Abnova (Taipei, Taiwan).…”

Section: Methodsmentioning

confidence: 99%

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

et al. 2016

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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). Inversely, augmented osteoclastogenesis and bone destruction was observed with NRF2 deficiency (Rana et al, 2012; Hyeon et al, 2013; Ibanez et al, 2014; Lippross et al, 2014; Sun et al, 2015).…”

Section: Mechanisms That Protect Against Oxidative Stressmentioning

confidence: 99%

“…One protective mechanism involves nuclear factor E2-related factor 2 (NRF2), a master regulatory transcription factor for the synthesis of cytoprotective enzymes. NRF2 has been reported to be a negative regulator of osteoclastogenesis (Kanzaki et al, 2013, 2014, 2015). …”

Section: Introductionmentioning

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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“…9 Excessive oxidative stress seems to play an important role in the destruction of periodontal tissues. 13 Previous studies have indicated that NFE2L2/NRF2 activation suppresses osteoclastogenesis, 14 it protects periodontal ligament stem cells from oxidative stress-related apoptosis, 15 and its down-regulation in oral neutrophils is associated with chronic periodontitis in humans. 12 The cytoprotective role of KEAP1 and NFE2L2/NRF2 in the reduction of inflammatory signaling and oxidative damage is highly important and has been reviewed recently.…”

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confidence: 99%