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

J Clin Invest. 2012 Jan;122(1):91-106. doi: 10.1172/JCI59466. Epub 2011 Dec 1.

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 types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Development / genetics
  • Bone Development / physiology
  • Bone Morphogenetic Protein 2 / administration & dosage*
  • Bone Morphogenetic Protein 2 / genetics
  • Bone Morphogenetic Protein 7 / administration & dosage*
  • CREB-Binding Protein / deficiency
  • CREB-Binding Protein / genetics*
  • Core Binding Factor Alpha 1 Subunit / deficiency
  • Core Binding Factor Alpha 1 Subunit / genetics
  • Cyclic AMP Response Element-Binding Protein / deficiency
  • Cyclic AMP Response Element-Binding Protein / genetics
  • Disease Models, Animal
  • Female
  • Fetal Therapies / methods*
  • Gene Expression Regulation, Developmental
  • Humans
  • Insulin / metabolism
  • Insulin-Like Growth Factor I / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Mutant Strains
  • Mutation
  • Osteoblasts / drug effects
  • Osteoblasts / metabolism
  • Osteoblasts / pathology
  • Pregnancy
  • Protein Serine-Threonine Kinases / deficiency
  • Protein Serine-Threonine Kinases / genetics*
  • Protein Serine-Threonine Kinases / metabolism
  • Pyruvate Dehydrogenase Acetyl-Transferring Kinase
  • Recombinant Proteins / administration & dosage
  • Rubinstein-Taybi Syndrome / embryology
  • Rubinstein-Taybi Syndrome / genetics*
  • Rubinstein-Taybi Syndrome / metabolism
  • Rubinstein-Taybi Syndrome / therapy*
  • Signal Transduction
  • Uterus

Substances

  • BMP2 protein, human
  • BMP7 protein, human
  • Bmp2 protein, mouse
  • Bone Morphogenetic Protein 2
  • Bone Morphogenetic Protein 7
  • Core Binding Factor Alpha 1 Subunit
  • Creb1 protein, mouse
  • Cyclic AMP Response Element-Binding Protein
  • Insulin
  • PDK1 protein, human
  • Pdk1 protein, mouse
  • Pyruvate Dehydrogenase Acetyl-Transferring Kinase
  • Recombinant Proteins
  • Runx2 protein, mouse
  • Insulin-Like Growth Factor I
  • CREB-Binding Protein
  • Crebbp protein, mouse
  • Protein Serine-Threonine Kinases