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
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
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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细胞胞质-1核因子减少的机制
DOI：
10.1096/fj.201700177r
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发表时间：
2017
期刊：
影响因子：
4.8
通讯作者：
and Tsukuba T
中科院分区：
文献类型：
--
作者：
Sakai E.;Morita M.;Ohuchi M.;Kido MA.;Fukuma Y.;Nishishita K.;Okamoto K.;Itoh K.;Yamamoto M;and Tsukuba T
Kelch样ECH相关蛋白1（Keap 1）与核因子E2 p45相关因子2（Nrf 2）结合，Nrf 2是一种抗氧化酶的转录因子，可抑制Nrf 2的活化。氧化应激在许多疾病中的作用支持了与Nrf 2激活相关的过程可能提供治疗潜力的可能性。Nrf 2缺陷通过激活NF-κB配体受体激活剂（RANKL）介导的信号传导诱导破骨细胞生成，这是骨丢失的原因;然而，Keap 1缺陷的影响仍不清楚。通过使用Keap 1缺陷的新生小鼠，我们观察到距骨和跟骨骨形成部分延迟，破骨细胞数量减少，但没有严重的大体异常。此外，Keap 1缺陷型巨噬细胞无法通过RANKL介导的信号转导和活化T细胞胞质核因子1（NFATc 1）（一种参与破骨细胞生成的关键转录因子）表达的减弱在体外分化为破骨细胞。此外，Keap 1缺陷上调了NFATc 1负调节因子Mafb的表达。RANKL诱导的线粒体基因表达是下调IFN调节因子8（IRF-8）（NFATc 1的负转录调节因子）所必需的。我们的研究结果表明，Keap 1缺陷下调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，上调Irf 8表达。这些结果表明，Keap 1/Nrf 2轴在NFATc 1表达和破骨细胞生成进展中起着关键作用。Sakai，E.，Morita，M.，Ohuchi，M.，Kido，M.一、Yellow，Y.，Nishishita，K.，Okamoto，K.，Itoh，K.，山本，M.，Tsukuba，T. 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细胞胞质1核因子减少的机制FASEB J. 31，4011-4022（2017）。www.fasebj.org-Sakai，Eiko，Morita，Masanobu，Ohuchi，Masahiro，Kido，瑞穗A.，Kazuuma，Yutaka，Nishishita，Kazuhisa，Okamoto，Kuniaki，Itoh，Ken，Yamamoto，Masayuki，Tsukuba，Takayuki，缺乏Kelch样ECH相关蛋白1对骨骼组织的影响：破骨细胞生成过程中活化T细胞胞质1核因子减少的机制。FASEB J. 31，4011-4022（2017）
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 reducedin vivowithout severe gross abnormalities. In addition, Keap1‐deficient macrophages were unable to differentiate into osteoclastsin vitro viaattenuation 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 ofMafb, 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‐regulatedIrf8expression. 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. FASEB J. 31, 4011–4022 (2017). www.fasebj.org—Sakai, Eiko, Morita, Masanobu, Ohuchi, Masahiro, Kido, Mizuho A., Fukuma, Yutaka, Nishishita, Kazuhisa, Okamoto, Kuniaki, Itoh, Ken, Yamamoto, Masayuki, Tsukuba, Takayuki, 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. FASEB J. 31, 4011–4022 (2017)