Kindlin-2 controls TGF-β signalling and Sox9 expression to regulate chondrogenesis.
Kindlin-2 controls TGF-β signalling and Sox9 expression to regulate chondrogenesis.
复制标题
Kindlin-2 控制 TGF-β 信号传导和 Sox9 表达来调节软骨形成
DOI：
10.1038/ncomms8531
复制
发表时间：
2015-07-07
影响因子：
16.6
通讯作者：
Xiao, Guozhi
中科院分区：
文献类型：
--
作者：
Wu, Chuanyue;Jiao, Hongli;Lai, Yumei;Zheng, Wei;Chen, Ka;Qu, Hong;Deng, Weimin;Song, Pingping;Zhu, Ke;Cao, Huiling;Galson, Deborah L.;Fan, Jie;Im, Hee-Jeong;Liu, Yujie;Chen, Ju;Chen, Di;Xiao, Guozhi
控制骨骼发生的信号还不完全清楚。在这里，我们表明，删除Kindlin-2在Prx 1表达间充质祖细胞的小鼠导致新生儿死亡，软骨发育不良和颅骨穹窿的损失。Kindlin-2消融通过减少细胞增殖和增加细胞凋亡来降低软骨细胞密度，并破坏柱形成，从而损害初级骨化中心的形成并导致严重的肢体缩短。值得注意的是，Kindlin-2不仅定位于粘着斑，而且定位于软骨细胞的细胞核。Kindlin-2的缺失减少Sox 9的表达，而Kindlin-2的过表达增加Sox 9的表达。此外，Sox 9的过表达在体外恢复了由Kindlin-2缺失诱导的软骨形成分化的缺陷。此外，Kindlin-2消融抑制TGF-β1诱导的Smad 2磷酸化和软骨细胞分化。最后，在软骨细胞中删除Kindlin-2直接损害软骨细胞功能，导致小鼠进行性侏儒症和脊柱后凸。这些研究揭示了Kindlin-2以前未被认识的功能以及调节软骨细胞分化程序和软骨形成的机制。Kidlin是在细胞粘着斑中发现的蛋白质，在粘着斑中它们调节整联蛋白，并且在细胞核中它们的作用未知。在这里，作者表明Kindlin-2通过调节整合素b1活化和Sox 9和TGF-β核信号传导来控制软骨形成。
The signals that control skeletogenesis are incompletely understood. Here we show that deleting Kindlin-2 in Prx1-expressing mesenchymal progenitors in mice causes neonatal lethality, chondrodysplasia and loss of the skull vault. Kindlin-2 ablation reduces chondrocyte density by decreasing cell proliferation and increasing apoptosis, and disrupts column formation, thus impairing the formation of the primary ossification center and causing severe limb shortening. Remarkably, Kindlin-2 localizes to not only focal adhesions, but also to the nuclei of chondrocytes. Loss of Kindlin-2 reduces, while the overexpression of Kindlin-2 increases, Sox9 expression. Furthermore, the overexpression of Sox9 restores the defects in chondrogenic differentiation induced by Kindlin-2 deletion in vitro. In addition, Kindlin-2 ablation inhibits TGF-β1-induced Smad2 phosphorylation and chondrocyte differentiation. Finally, deleting Kindlin-2 in chondrocytes directly impairs chondrocyte functions, resulting in progressive dwarfism and kyphosis in mice. These studies uncover a previously unrecognized function for Kindlin-2 and a mechanism for regulation of the chondrocyte differentiation programme and chondrogenesis. The Kidlins are proteins found in cell focal adhesion sites where they regulate integrins, and in the nucleus where their role is unknown. Here the authors show that Kindlin-2 controls chondrogenesis by regulating integrin b1 activation and Sox9 and TGF-β nuclear signalling.
登录
查看更多内容
影响因子：
11.4
作者：
Lefebvre, V;Li, P;de Crombrugghe, B
通讯作者：
de Crombrugghe, B
影响因子：
10.5
作者：
Akiyama, H;Chaboissier, MC;de Crombrugghe, B
通讯作者：
de Crombrugghe, B
影响因子：
5.3
作者：
Lefebvre, V;Huang, WD;deCrombrugghe, B
通讯作者：
deCrombrugghe, B
影响因子：
4.5
作者：
Leung VY;Gao B;Leung KK;Melhado IG;Wynn SL;Au TY;Dung NW;Lau JY;Mak AC;Chan D;Cheah KS
通讯作者：
Cheah KS
影响因子：
1.5
作者：
Chen, Mo;Lichtler, Alexander C.;Chen, Di
通讯作者：
Chen, Di