c-Abl promotes osteoblast expansion by differentially regulating canonical and non-canonical BMP pat

Abstract

Defects in stem cell renewal or progenitor cell expansion underlie ageing-related diseases such as osteoporosis. Yet much remains unclear about the mechanisms regulating progenitor expansion. Here we show that the tyrosine kinase c-Abl plays an important role in osteoprogenitor expansion. c-Abl interacts with and phosphorylates BMPRIA and the phosphorylation differentially influences the interaction of BMPRIA with BMPRII and the Tab1–Tak1 complex, leading to uneven activation of Smad1/5/8 and Erk1/2, the canonical and non-canonical BMP pathways that direct the expression of p16INK4a. c-Abl deficiency shunts BMP signalling from Smad1/5/8 to Erk1/2, leading to p16INK4a upregulation and osteoblast senescence. Mouse genetic studies revealed that p16INK4a controls mesenchymal stem cell maintenance and osteoblast expansion and mediates the effects of c-Abl deficiency on osteoblast expansion and bone formation. These findings identify c-Abl as a regulator of BMP signalling pathways and uncover a role for c-Abl in p16INK4a expression and osteoprogenitor expansion. Li and colleagues report that c-Abl regulates the responses downstream of bone morphogenetic protein (BMP) that direct proliferation or senescence in osteoblasts. They show that phosphorylation of the BMP receptor BMPR1A by c-Abl promotes downstream Smad-mediated responses and osteoblast expansion, whereas in the absence of c-Abl, BMP activates Erk signalling, leading to p16INK4a-induced senescence.

Cite this article

Kua, HY., Liu, H., Leong, W. et al. c-Abl promotes osteoblast expansion by differentially regulating canonical and non-canonical BMP pathways and p16^INK4a expression. Nat Cell Biol 14, 727–737 (2012). https://doi.org/10.1038/ncb2528

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