| RRC ID |
45285
|
| 著者 |
Kanzaki H, Shinohara F, Kajiya M, Fukaya S, Miyamoto Y, Nakamura Y.
|
| タイトル |
Nuclear Nrf2 induction by protein transduction attenuates osteoclastogenesis.
|
| ジャーナル |
Free Radic Biol Med
|
| 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.
|
| 巻・号 |
77
|
| ページ |
239-48
|
| 公開日 |
2014-12-1
|
| DOI |
10.1016/j.freeradbiomed.2014.09.006
|
| PII |
S0891-5849(14)00425-0
|
| PMID |
25224039
|
| MeSH |
Active Transport, Cell Nucleus
Animals
Bone Density Conservation Agents / pharmacology*
Cell Line
Cell Nucleus / metabolism*
Male
Mice, Inbred C57BL
NF-E2-Related Factor 2 / metabolism*
Oligopeptides / pharmacology*
Osteoclasts / drug effects
Osteoclasts / physiology*
RANK Ligand / pharmacology
RANK Ligand / physiology
Reactive Oxygen Species / metabolism
|
| IF |
6.17
|
| 引用数 |
22
|
|
WOS 分野
|
BIOCHEMISTRY & MOLECULAR BIOLOGY
ENDOCRINOLOGY & METABOLISM
|
| リソース情報 |
| ヒト・動物細胞 |
RAW 264(RCB0535) |
