RANKL induces Bach1 nuclear import and attenuates Nrf2-mediated antioxidant enzymes, thereby augmenting intracellular reactive oxygen species signaling and osteoclastogenesis in mice.
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.
Maxillo-Oral Disorders, Tohoku University Hospital, Sendai, Japan; kanzaki-h@tsurumi-u.ac.jp.|Department of Orthodontics, School of Dental Medicine, Tsurumi University, Yokohama, Japan; and.
Hiroyuki
H
Kanzaki
Oral Microbiology, Tohoku University Graduate School of Dentistry, Sendai, Japan.
Fumiaki
F
Shinohara
Department of Orthodontics, School of Dental Medicine, Tsurumi University, Yokohama, Japan; and.
Kanako
K
Itohiya
Department of Orthodontics, School of Dental Medicine, Tsurumi University, Yokohama, Japan; and.
Yuuki
Y
Yamaguchi
Department of Orthodontics, School of Dental Medicine, Tsurumi University, Yokohama, Japan; and.
Yuta
Y
Katsumata
Department of Orthodontics, School of Dental Medicine, Tsurumi University, Yokohama, Japan; and.
Masazumi
M
Matsuzawa
Department of Orthodontics, School of Dental Medicine, Tsurumi University, Yokohama, Japan; and.
Sari
S
Fukaya
Department of Orthodontics, School of Dental Medicine, Tsurumi University, Yokohama, Japan; and.
Yutaka
Y
Miyamoto
Department of Orthodontics, School of Dental Medicine, Tsurumi University, Yokohama, Japan; and.
Satoshi
S
Wada
Department of Orthodontics, School of Dental Medicine, Tsurumi University, Yokohama, Japan; and.
Yoshiki
Y
Nakamura
D021581:Active Transport, Cell Nucleus / Q000502:physiology; D000818:Animals; D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism*; D002470:Cell Survival; D005786:Gene Expression Regulation / Q000502:physiology; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D010010:Osteoclasts / Q000502:physiology*; D053245:RANK Ligand / Q000235:genetics / Q000378:metabolism*; D000067996:RAW 264.7 Cells; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
C486316:Bach1 protein, mouse; D050976:Basic-Leucine Zipper Transcription Factors; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D053245:RANK Ligand; D017382:Reactive Oxygen Species; C505689:Tnfsf11 protein, mouse
JNK; NQO1; aminolevulinic acid; bone destruction; heme