C-ABL promotes osteoblast expansion through BMP signaling pathways

Abstract

A defect in stem cell renewal or progenitor cell expansion might cause aging related diseases such as osteoporosis. We report here that c-Abl-/-osteoblasts show premature senescence due to up-regulation of p16INK4a. p16INK4a expression can be regulated by BMPs, which are major regulators of bone remodeling, through Erk1/2 and Smad1/5/8-Id1 in opposing ways. c-Abl deficiency shunts BMP signaling from Smad1/5/8 to Erk1/2, leading to the up-regulation of p16INK4a. Further studies suggest that c-Abl regulates these two signaling events by phosphorylating BMPRIA mainly on Y453/467, which differentially influences its interaction with BMPRII and Tab1-Tak1 complex. These findings place c-Abl in BMP signaling pathways and establish its importance in osteoprogenitor expansion, linking osteoprogenitor senescence to senile osteoporosis.