Format

Send to

Choose Destination
Nat Commun. 2015 Jul 7;6:7531. doi: 10.1038/ncomms8531.

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

Author information

1
1] Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA. [2] Department of Biology and Shenzhen Key Laboratory of Cell Microenvironment, South University of Science and Technology of China, Shenzhen 518055, China.
2
Department of Biochemistry, Rush University Medical Center, Chicago, Illinois 60612, USA.
3
Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.
4
Department of Biology and Shenzhen Key Laboratory of Cell Microenvironment, South University of Science and Technology of China, Shenzhen 518055, China.
5
Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15240, USA.
6
Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15240, USA.
7
Department of Medicine, University of California San Diego, La Jolla, California 92093, USA.
8
1] Department of Biology and Shenzhen Key Laboratory of Cell Microenvironment, South University of Science and Technology of China, Shenzhen 518055, China. [2] Department of Biochemistry, Rush University Medical Center, Chicago, Illinois 60612, USA.

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.

PMID:
26151572
PMCID:
PMC4498276
DOI:
10.1038/ncomms8531
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center