Sakai Eiko, Morita Masanobu, Ohuchi Masahiro, Kido Mizuho A, Fukuma Yutaka, Nishishita Kazuhisa, Okamoto Kuniaki, Itoh Ken, Yamamoto Masayuki, Tsukuba Takayuki
Division of Dental Pharmacology, Department of Developmental and Reconstructive Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan;
Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan.
FASEB J. 2017 Sep;31(9):4011-4022. doi: 10.1096/fj.201700177R. Epub 2017 May 17.
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 without severe gross abnormalities. In addition, Keap1-deficient macrophages were unable to differentiate into osteoclasts 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 , 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 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.
Kelch样ECH相关蛋白1（Keap1）与核因子E2 p45相关因子2（Nrf2）结合，Nrf2是抗氧化酶的转录因子，可抑制Nrf2的激活。氧化应激在许多疾病中的作用支持了与Nrf2激活相关的过程可能具有治疗潜力的可能性。Nrf2缺乏通过激活核因子κB受体激活剂配体（RANKL）介导的信号传导诱导破骨细胞生成，而破骨细胞生成是导致骨质流失的原因；然而，Keap1缺乏的影响仍不清楚。通过使用Keap1缺陷的新生小鼠，我们观察到距骨和跟骨的骨形成部分受阻，破骨细胞数量减少，且无严重的大体异常。此外，Keap1缺陷的巨噬细胞无法分化为破骨细胞，RANKL介导的信号传导和活化T细胞核因子细胞质1（NFATc1）的表达减弱，NFATc1是参与破骨细胞生成的关键转录因子。此外，Keap1缺乏上调了NFATc1的负调节因子的表达。RANKL诱导的线粒体基因表达是下调NFATc1的负转录调节因子干扰素调节因子8（IRF-8）所必需的。我们的结果表明Keap1缺乏下调了过氧化物酶体增殖物激活受体γ共激活因子1β和线粒体基因表达，并上调了的表达。这些结果表明，Keap1/Nrf2轴在NFATc1表达和破骨细胞生成进展中起关键作用。-酒井英、森田真、大内真、木户麻里爱、深间洋、西下启、冈本健、伊藤健、山本真、筑波哲。Kelch样ECH相关蛋白1缺乏对骨骼组织的影响：破骨细胞生成过程中活化T细胞核因子细胞质1减少的机制。
