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