RRC ID 48723
著者 Sakai E, Morita M, Ohuchi M, Kido MA, Fukuma Y, Nishishita K, Okamoto K, Itoh K, Yamamoto M, Tsukuba T.
タイトル Effects of deficiency of Kelch-like ECH-associated protein 1 on skeletal organization: a mechanism for diminished nuclear factor of activated T cells cytoplasmic 1 during osteoclastogenesis.
ジャーナル FASEB J
Abstract Kelch-like ECH-associated protein 1 (Keap1) binds to nuclear factor E2 p45-related factor 2 (Nrf2), a transcription factor for antioxidant enzymes, to suppress Nrf2 activation. The role of oxidative stress in many diseases supports the possibility that processes that are associated with Nrf2 activation might offer therapeutic potential. Nrf2 deficiency induces osteoclastogenesis, which is responsible for bone loss, by activating receptor activator of NF-κB ligand (RANKL)-mediated signaling; however, the effects of Keap1 deficiency remain unclear. By using Keap1-deficient newborn mice, we observed that talus and calcaneus bone formation was partially retarded and that osteoclast number was reduced in vivo without severe gross abnormalities. In addition, Keap1-deficient macrophages were unable to differentiate into osteoclasts in vitrovia attenuation of RANKL-mediated signaling and expression of nuclear factor of activated T cells cytoplasmic 1 (NFATc1), a key transcription factor that is involved in osteoclastogenesis. Furthermore, Keap1 deficiency up-regulated the expression of Mafb, a negative regulator of NFATc1. RANKL-induced mitochondrial gene expression is required for down-regulation of IFN regulatory factor 8 (IRF-8), a negative transcriptional regulator of NFATc1. Our results indicate that Keap1 deficiency down-regulated peroxisome proliferator-activated receptor-γ coactivator 1β and mitochondrial gene expression and up-regulated Irf8 expression. These results suggest that the Keap1/Nrf2 axis plays a critical role in NFATc1 expression and osteoclastogenic progression.-Sakai, E., Morita, M., Ohuchi, M., Kido, M. A., Fukuma, Y., Nishishita, K., Okamoto, K., Itoh, K., Yamamoto, M., Tsukuba, T. Effects of deficiency of Kelch-like ECH-associated protein 1 on skeletal organization: a mechanism for diminished nuclear factor of activated T cells cytoplasmic 1 during osteoclastogenesis.
巻・号 31(9)
ページ 4011-4022
公開日 2017-9-1
DOI 10.1096/fj.201700177R
PII fj.201700177R
PMID 28515152
MeSH Animals Animals, Newborn Down-Regulation Gene Expression Regulation / physiology* Interferon Regulatory Factors / genetics Interferon Regulatory Factors / metabolism Kelch-Like ECH-Associated Protein 1 / genetics Kelch-Like ECH-Associated Protein 1 / metabolism* Macrophages MafB Transcription Factor / genetics MafB Transcription Factor / metabolism Mice Mice, Knockout Mitochondria / metabolism NF-E2-Related Factor 2 / genetics NF-E2-Related Factor 2 / metabolism* NFATC Transcription Factors / genetics NFATC Transcription Factors / metabolism* Nuclear Proteins / genetics Nuclear Proteins / metabolism Osteoblasts / physiology* Osteogenesis / genetics Osteogenesis / physiology* RANK Ligand / genetics RANK Ligand / metabolism Transcription Factors / genetics Transcription Factors / metabolism Up-Regulation
IF 4.966
引用数 6
リソース情報
実験動物マウス RBRC01388 RBRC01390