Kindlin-2 controls TGF-β signalling and Sox9 expression to regulate chondrogenesis

Chuanyue Wu (), Hongli Jiao, Yumei Lai, Wei Zheng, Ka Chen, Hong Qu, Weimin Deng, Pingping Song, Ke Zhu, Huiling Cao, Deborah L. Galson, Jie Fan, Hee-Jeong Im, Yujie Liu, Ju Chen, Di Chen and Guozhi Xiao ()
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Chuanyue Wu: University of Pittsburgh
Hongli Jiao: Rush University Medical Center
Yumei Lai: Rush University Medical Center
Wei Zheng: Rush University Medical Center
Ka Chen: University of Pittsburgh
Hong Qu: University of Pittsburgh
Weimin Deng: Rush University Medical Center
Pingping Song: Rush University Medical Center
Ke Zhu: Rush University Medical Center
Huiling Cao: South University of Science and Technology of China
Deborah L. Galson: University of Pittsburgh
Jie Fan: University of Pittsburgh
Hee-Jeong Im: Rush University Medical Center
Yujie Liu: University of California San Diego
Ju Chen: University of California San Diego
Di Chen: Rush University Medical Center
Guozhi Xiao: South University of Science and Technology of China

Nature Communications, 2015, vol. 6, issue 1, 1-13

Abstract: Abstract 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.

Date: 2015
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DOI: 10.1038/ncomms8531

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