c-Abl promotes osteoblast expansion by differentially regulating canonical and non-canonical BMP pathways and p16INK4a expression

Nat Cell Biol. 2012 Jun 24;14(7):727-37. doi: 10.1038/ncb2528.

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 p16(INK4a). c-Abl deficiency shunts BMP signalling from Smad1/5/8 to Erk1/2, leading to p16(INK4a) upregulation and osteoblast senescence. Mouse genetic studies revealed that p16(INK4a) 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 p16(INK4a) expression and osteoprogenitor expansion.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Amino Acid Sequence
  • Animals
  • Bone Morphogenetic Protein Receptors, Type I / genetics
  • Bone Morphogenetic Protein Receptors, Type I / metabolism
  • Bone Morphogenetic Protein Receptors, Type II / metabolism
  • Bone Morphogenetic Proteins / metabolism*
  • Cell Proliferation*
  • Cells, Cultured
  • Cellular Senescence*
  • Cyclin-Dependent Kinase Inhibitor p16 / deficiency
  • Cyclin-Dependent Kinase Inhibitor p16 / genetics
  • Cyclin-Dependent Kinase Inhibitor p16 / metabolism*
  • Enzyme Activation
  • Genotype
  • Inhibitor of Differentiation Protein 1 / metabolism
  • MAP Kinase Kinase Kinases / metabolism
  • Mesenchymal Stem Cells / enzymology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Molecular Sequence Data
  • Osteoblasts / enzymology*
  • Phenotype
  • Phosphorylation
  • Proto-Oncogene Proteins c-abl / genetics
  • Proto-Oncogene Proteins c-abl / metabolism*
  • Signal Transduction
  • Smad1 Protein / metabolism
  • Smad5 Protein / metabolism
  • Smad8 Protein / metabolism
  • Time Factors
  • Transfection
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • Bone Morphogenetic Proteins
  • Cdkn2a protein, mouse
  • Cyclin-Dependent Kinase Inhibitor p16
  • Idb1 protein, mouse
  • Inhibitor of Differentiation Protein 1
  • Smad1 Protein
  • Smad1 protein, mouse
  • Smad5 Protein
  • Smad5 protein, mouse
  • Smad8 Protein
  • Smad9 protein, mouse
  • Tab1 protein, mouse
  • Tumor Suppressor Protein p53
  • Proto-Oncogene Proteins c-abl
  • Mapk1 protein, mouse
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • MAP Kinase Kinase Kinases
  • MAP kinase kinase kinase 7
  • Bmpr1a protein, mouse
  • Bmpr2 protein, mouse
  • Bone Morphogenetic Protein Receptors, Type I
  • Bone Morphogenetic Protein Receptors, Type II