动力蛋白亚基DCTN1通过Cdc42 / PAK2途径控制破骨细胞生成。,Experimental & Molecular Medicine

当前位置： X-MOL 学术 › Exp. Mol. Med. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

动力蛋白亚基DCTN1通过Cdc42 / PAK2途径控制破骨细胞生成。
Experimental & Molecular Medicine ( IF 9.5 ) Pub Date : 2020-03-24 , DOI: 10.1038/s12276-020-0406-0
Yong Deok Lee ₁ , Bongjun Kim ₁ , Suhan Jung ₁ , Haemin Kim _{1,

2} , Min Kyung Kim ₁ , Jun-Oh Kwon ₁ , Min-Kyoung Song ₁ , Zang Hee Lee ₁ , Hong-Hee Kim ₁

Affiliation

破骨细胞（OCs）是专门用于骨吸收的细胞，是通过RANKL控制的分化过程从单核细胞/巨噬细胞前体产生的。在这里，我们显示DCTN1，动力蛋白复合物的关键组成部分，在OC分化中起重要作用。DCTN1的表达被RANKL上调。基因敲低对DCTN1表达的抑制作用抑制了OC的形成，骨吸收以及NFATc1和c-Fos（破骨细胞形成的关键转录因子）的诱导。更重要的是，DCTN1沉默抑制了RANKL对Cdc42的激活。组成型活性Cdc42的强制表达恢复了具有DCTN1缺失的前体的OC分化。此外，发现PAK2被RANKL激活并在Cdc42的下游起作用。DCTN1-Cdc42轴也抑制细胞凋亡和caspase-3激活。此外，在骨侵蚀动物模型中证实了DCTN1敲低的抗破骨细胞作用。有趣的是，DCTN1的过表达也不利于OC的分化，这表明DCTN1应该被调节在适当的水平以有效地破骨细胞形成。总的来说，我们的结果表明DCTN1参与破骨细胞形成过程中Cdc42 / PAK2信号的激活和细胞凋亡的抑制。

"点击查看英文标题和摘要"

The dynactin subunit DCTN1 controls osteoclastogenesis via the Cdc42/PAK2 pathway.

Osteoclasts (OCs), cells specialized for bone resorption, are generated from monocyte/macrophage precursors by a differentiation process governed by RANKL. Here, we show that DCTN1, a key component of the dynactin complex, plays important roles in OC differentiation. The expression of DCTN1 was upregulated by RANKL. The inhibition of DCTN1 expression by gene knockdown suppressed OC formation, bone resorption, and the induction of NFATc1 and c-Fos, critical transcription factors for osteoclastogenesis. More importantly, the activation of Cdc42 by RANKL was inhibited upon DCTN1 silencing. The forced expression of constitutively active Cdc42 restored the OC differentiation of precursors with DCTN1 deletion. In addition, PAK2 was found to be activated by RANKL and to function downstream of Cdc42. The DCTN1-Cdc42 axis also inhibited apoptosis and caspase-3 activation. Furthermore, the anti-osteoclastogenic effect of DCTN1 knockdown was verified in an animal model of bone erosion. Intriguingly, DCTN1 overexpression was also detrimental to OC differentiation, suggesting that DCTN1 should be regulated at the appropriate level for effective osteoclastogenesis. Collectively, our results reveal that DCTN1 participates in the activation of Cdc42/PAK2 signaling and the inhibition of apoptosis during osteoclastogenesis.

更新日期：2020-04-24

点击分享查看原文

点击收藏

公开下载

阅读更多本刊新发论文