Kindlin-2 controls TGF-β signalling and Sox9 expression to regulate chondrogenesis.
Chuanyue WuHongli JiaoYumei LaiWei ZhengKa ChenHong QuWeimin DengPingping SongKe ZhuHuiling CaoDeborah L GalsonJie FanHee-Jeong ImYujie LiuJu ChenDi ChenGuozhi XiaoPublished in: Nature communications (2015)
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.
Keyphrases
- cell proliferation
- transcription factor
- stem cells
- poor prognosis
- transforming growth factor
- multiple sclerosis
- type diabetes
- mesenchymal stem cells
- binding protein
- cell death
- drug induced
- skeletal muscle
- study protocol
- mass spectrometry
- insulin resistance
- high fat diet induced
- extracellular matrix
- atrial fibrillation
- tandem mass spectrometry