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.
Highlights
IntroductionWe show that deleting Kindlin-2 in Prx1-expressing mesenchymal progenitors in mice causes neonatal lethality, chondrodysplasia and loss of the skull vault
The signals that control skeletogenesis are incompletely understood
In endochondral ossification, which forms most of the other bones, including all long bones and vertebrae, an intermediate cartilaginous template is first formed through a process that involves mesenchymal stem cells (MSCs) condensation, chondrocyte proliferation, hypertrophy and apoptosis; this is followed by replacement by bone in the adjacent metaphysis through multiple steps, including new blood vessel invasion, osteoclast differentiation and digestion of the calcified cartilage and osteoblastogenesis from the perichondrial cells and bone formation[2]
Summary
We show that deleting Kindlin-2 in Prx1-expressing mesenchymal progenitors in mice causes neonatal lethality, chondrodysplasia and loss of the skull vault. Deleting Kindlin-2 in chondrocytes directly impairs chondrocyte functions, resulting in progressive dwarfism and kyphosis in mice. We demonstrate that conditional ablation of Kindlin-2 in Prx1-expressing limb and head mesenchymal progenitors in mice results in neonatal lethality, severe chondrodysplasia and complete loss of the skull vault. Loss of Kindlin-2 inhibits chondrocyte proliferation, increases chondrocyte apoptosis and disrupts the column formation, which together impairs formation of the primary ossification centre (POC) of the long bones and results in limb and digit shortening. Kindlin-2 expression is required for control of intramembranous ossification, as demonstrated by a complete loss of the skull vault and severe hypoplastic clavicles in the mutant mice. Our results shed important new light on the functions of Kindlin-2 and its mode of action in skeletogenesis
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