The Keap1/Nrf2 Protein Axis Plays a Role in Osteoclast Differentiation by Regulating Intracellular Reactive Oxygen Species Signaling

Background Within cells, there is a narrow concentration threshold that governs whether reactive oxygen species (ROS) induce toxicity or act as second messengers. Scope of review We discuss current understanding of how ROS arise, facilitate cell signaling, cause toxicities and disease related to abnormal cell differentiation and those (primarily) sulfur based pathways that provide nucleophilicity to offset these effects. Primary conclusions Cellular redox homeostasis mediates a plethora of cellular pathways that determine life and death events. For example, ROS intersect with GSH based enzyme pathways to influence cell differentiation, a process integral to normal hematopoiesis, but also affecting a number of diverse cell differentiation related human diseases. Recent attempts to manage such pathologies have focused on intervening in some of these pathways, with the consequence that differentiation therapy targeting redox homeostasis has provided a platform for drug discovery and development. General Significance The balance between electrophilic oxidative stress and protective biomolecular nucleophiles predisposes the evolution of modern life forms. Imbalances of the two can produce aberrant redox homeostasis with resultant pathologies. Understanding the pathways involved provides opportunities to consider interventional strategies.

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“…Keap1/Nrf2 regulates osteoclast differentiation through modulating ROS by expression of cytoprotective enzymes [82];…”

Section: Figurementioning

confidence: 99%

Oxidative stress, redox regulation and diseases of cellular differentiation

Zhang

Townsend

et al. 2015

Biochimica et Biophysica Acta (BBA) - General Subjects

206

142

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“…Among them, transcriptional factor nuclear factor E2-related factor 2 (Nrf2) transcriptionally controls gene expression of many antioxidant enzymes (8)(9)(10)(11). Previously, we reported that Nrf2-dependent expression of antioxidant enzymes was attenuated during RANKLdependent osteoclastogenesis via reduction of nuclear Nrf2 (12), although the regulatory mechanism is still unknown.…”

mentioning

confidence: 99%

“…Bach1 allows antioxidant enzyme gene induction upon its inactivation; that is, release of Bach1 from the antioxidant response element in the promoter region and subsequent replacement by Nrf2 (15,16). Whereas the role of Nrf2 in osteoclastogenesis (12) and regulation of Nrf2 activity by Bach1 (17) were reported, the relationship between ABBREVIATIONS: ALA, 5-aminolevulinic acid; Bach1, BTB and CNC homology 1; HO1, heme-oxygenase 1; microCT, micro-computed tomography; NQO1, NAD(P) quinone reductase; Nrf2, nuclear factor E2-related factor 2; OD 450/490 , optical density at 450/490 nm; PBS-T, 0.5% Tween-20 in PBS; RANKL, receptor activator of nuclear factor-kB ligand; ROS, reactive oxygen species; SFC, sodium ferrous citrate; TRAP, tartrate-resistant acid phosphatase Bach1 and RANKL-mediated osteoclastogenesis is poorly understood.…”

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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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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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“…In particular, the NRF2-mediated regulation of cell proliferation and differentiation has gained attention as a possible mechanism by which environmental stress can influence cell fate determination. For example, NRF2 modulates the differentiation of osteoclasts (10,11), myeloid cells (12), and esophageal basal cells (13). Previously, we and other groups found that NRF2 increases the number of intrahepatic cholangiocytes (14) and promotes hepatocyte proliferation during liver regeneration and reactive hypertrophy (15,16).…”

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confidence: 99%

NRF2 Activation Impairs Quiescence and Bone Marrow Reconstitution Capacity of Hematopoietic Stem Cells

Murakami

Suzuki

Harigae

et al. 2017

Molecular and Cellular Biology

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Tissue stem cells are maintained in quiescence under physiological conditions but proliferate and differentiate to replenish mature cells under stressed conditions. The KEAP1-NRF2 system plays an essential role in stress response and cytoprotection against redox disturbance. To clarify the role of the KEAP1-NRF2 system in tissue stem cells, we focused on hematopoiesis in this study and used Keap1-deficient mice to examine the effects of persistent activation of NRF2 on long-term hematopoietic stem cells (LT-HSCs). We found that persistent activation of NRF2 due to Keap1 deficiency did not change the number of LT-HSCs but reduced their quiescence in steady-state hematopoiesis. During hematopoietic regeneration after bone marrow (BM) transplantation, persistent activation of NRF2 reduced the BM reconstitution capacity of LT-HSCs, suggesting that NRF2 reduces the quiescence of LT-HSCs and promotes their differentiation, leading to eventual exhaustion. Transient activation of NRF2 by an electrophilic reagent also promotes the entry of LT-HSCs into the cell cycle. Taken together, our findings show that NRF2 drives the cell cycle entry and differentiation of LT-HSCs at the expense of their quiescence and maintenance, an effect that appears to be beneficial for prompt recovery from blood loss. We propose that the appropriate control of NRF2 activity by KEAP1 is essential for maintaining HSCs and guarantees their stress-induced regenerative response.

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The Keap1/Nrf2 Protein Axis Plays a Role in Osteoclast Differentiation by Regulating Intracellular Reactive Oxygen Species Signaling

Cited by 148 publications

References 46 publications

Oxidative stress, redox regulation and diseases of cellular differentiation

Oxidative stress, redox regulation and diseases of cellular differentiation

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

NRF2 Activation Impairs Quiescence and Bone Marrow Reconstitution Capacity of Hematopoietic Stem Cells

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