Administration of BMP2/7 in utero partially reverses Rubinstein-Taybi syndrome-like skeletal defects induced by Pdk1 or Cbp mutations in mice. Academic Article uri icon

Overview

abstract

  • Mutations in the coactivator CREB-binding protein (CBP) are a major cause of the human skeletal dysplasia Rubinstein-Taybi syndrome (RTS); however, the mechanism by which these mutations affect skeletal mineralization and patterning is unknown. Here, we report the identification of 3-phosphoinositide-dependent kinase 1 (PDK1) as a key regulator of CBP activity and demonstrate that its functions map to both osteoprogenitor cells and mature osteoblasts. In osteoblasts, PDK1 activated the CREB/CBP complex, which in turn controlled runt-related transcription factor 2 (RUNX2) activation and expression of bone morphogenetic protein 2 (BMP2). These pathways also operated in vivo, as evidenced by recapitulation of RTS spectrum phenotypes with osteoblast-specific Pdk1 deletion in mice (Pdk1osx mice) and by the genetic interactions observed in mice heterozygous for both osteoblast-specific Pdk1 deletion and either Runx2 or Creb deletion. Finally, treatment of Pdk1osx and Cbp+/- embryos with BMPs in utero partially reversed their skeletal anomalies at birth. These findings illustrate the in vivo function of the PDK1-AKT-CREB/CBP pathway in bone formation and provide proof of principle for in utero growth factor supplementation as a potential therapy for skeletal dysplasias.

publication date

  • December 1, 2011

Research

keywords

  • Bone Morphogenetic Protein 2
  • Bone Morphogenetic Protein 7
  • CREB-Binding Protein
  • Fetal Therapies
  • Protein Serine-Threonine Kinases
  • Rubinstein-Taybi Syndrome

Identity

PubMed Central ID

  • PMC3248303

Scopus Document Identifier

  • 84855464261

Digital Object Identifier (DOI)

  • 10.1126/science.1126313

PubMed ID

  • 22133875

Additional Document Info

volume

  • 122

issue

  • 1