FOXO1 inhibits osteoclastogenesis partially by antagnozing MYC.
FOXO1 inhibits osteoclastogenesis partially by antagnozing MYC.
复制标题
FOXO1 部分通过拮抗 MYC 来抑制破骨细胞生成。
DOI：
10.1038/srep16835
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发表时间：
2015-11-16
影响因子：
4.6
通讯作者：
Li F
中科院分区：
文献类型：
--
作者：
Tan P;Guan H;Xie L;Mi B;Fang Z;Li J;Li F
FOXO转录因子尤其是FOXO 1在骨发育和骨重建中具有重要作用。FOXO对成骨细胞谱系的调节被认为是阶段特异性的或环境依赖性的。有趣的是，最近关于FOXO在破骨细胞生成中所起作用的研究得出了不同的结论。Bartell等人表明，FOXO部分通过上调H2 O2失活酶过氧化氢酶抑制破骨细胞生成和骨吸收。Wang等人证明FOXO 1激活破骨细胞形成。在本研究中，我们证实了Bartell等人的结果，即RANKL刺激后FOXO 1表达降低; FOXO 1抑制促进破骨细胞分化和活性，FOXO 1激活抑制破骨细胞分化和活性; FOXO 1对破骨细胞生成的抑制作用部分由ROS介导，因为ROS清除剂处理取消了FOXO 1抑制对破骨细胞生成的作用。我们进一步研究了FOXO 1抑制破骨细胞生成的机制。我们发现FOXO 1抑制可调节MAPK、NF-κB和AP-1。最后，我们证明了FOXO 1对破骨细胞形成的抑制作用部分是由MYC抑制介导的，MYC抑制几乎完全消除了FOXO 1对破骨细胞生成的抑制作用。总之，我们的研究证实FOXO 1作为破骨细胞生成的细胞自主抑制剂。
FOXO transcription factors especially FOXO1 have profound roles in bone development and remodeling. The regulation of cells of the osteoblast lineage by FOXOs is suggested to be stage-specific or context dependent. Intriguingly, recent studies on the role played by FOXOs in osteoclastogenesis reached different conclusion. Bartell et al. showed that FOXOs restrained osteoclastogenesis and bone resorption partially by upregulation of the H2O2-inactivating enzyme catalase. Wang et al. demonstrated that FOXO1 activated osteoclast formation. In the present study, we confirmed the results of Bartell et al. that FOXO1 expression was reduced upon stimulation of RANKL; FOXO1 inhibition promoted and FOXO1 activation repressed, osteoclast differentiation and activity; the inhibitory effect of FOXO1 on osteoclastogenesis was partially mediated by ROS since treatment with ROS scavengers cancelled the effect of FOXO1 inhibition on osteoclastogenesis. We further investigated the mechanisms responsible for repressed osteoclastogenesis by FOXO1. We found that FOXO1 inhibition modulated MAPKs, NF-κB and AP-1. Finally, we proved that the inhibitory effect of FOXO1 on osteoclast formation was partially mediated by MYC suppression by showing that MYC repression almost totally abrogated the effect of FOXO1 inhibition on osteoclastogenesis. To conclude, our study confirmed FOXO1 as a cell-autonomous inhibitor of osteoclastogenesis.