Nuclear nrf2 induction by protein transduction attenuates osteoclastogenesis

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

    Research output: Contribution to journalArticlepeer-review

    25 Citations (Scopus)

    Abstract

    It has been reported that reactive oxygen species (ROS) play a role as intracellular signaling molecules in RANKL stimulation. Previously we demonstrated that induction of cytoprotective enzyme expression by Nrf2-gene transfer successfully ameliorated RANKL-dependent osteoclastogenesis. In the present study, we hypothesized that Nrf2 activation by inhibiting ubiquitination and degradation of Nrf2 by ETGE-peptide would induce Nrf2-dependent cytoprotective enzyme expression, attenuate ROS signaling, and thereby inhibit RANKL-dependent osteoclastogenesis. ETGE-peptide containing a cell-permeable sequence (seven consecutive arginine; 7R-ETGE) was applied to a mouse macrophage cell-line RAW 264.7 cell or a primary macrophage culture. ETGE-peptide prevents Keap1 from binding to Nrf2. Nrf2 nuclear translocation and Nrf2-dependent cytoprotective enzyme induction was observed. The effects of 7R-ETGE on RANKL-dependent induction of intracellular ROS levels and osteoclastogenesis were examined. Finally, the protective effect of 7R-ETGE on RANKL-mediated bone destruction was investigated in mice. 7R-ETGE dose-dependently induced nuclear Nrf2, followed by the induction of cytoprotective enzyme expression at both the gene and protein level. 7R-ETGE inhibited upregulation of intracellular ROS levels by RANKL stimulation, and osteoclastogenesis was attenuated. Of particular interest was that local injection of 7R-ETGE ameliorated RANKL-mediated bone destruction. Local induction of nuclear Nrf2 by protein transduction is a potential novel therapeutic target for bone destruction diseases such as periodontitis and rheumatoid arthritis.

    Original languageEnglish
    Pages (from-to)239-248
    Number of pages10
    JournalFree Radical Biology and Medicine
    Volume77
    DOIs
    Publication statusPublished - 2014 Dec

    Keywords

    • Cytoprotective enzyme
    • Nrf2
    • Osteoclast
    • Oxidative stress
    • RANKL
    • ROS

    ASJC Scopus subject areas

    • Biochemistry
    • Physiology (medical)

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