Title | Administration of BMP2/7 in utero partially reverses Rubinstein-Taybi syndrome-like skeletal defects induced by Pdk1 or Cbp mutations in mice. |
Publication Type | Journal Article |
Year of Publication | 2012 |
Authors | Shim J-H, Greenblatt MB, Singh A, Brady N, Hu D, Drapp R, Ogawa W, Kasuga M, Noda T, Yang S-H, Lee S-K, Rebel VI, Glimcher LH |
Journal | J Clin Invest |
Volume | 122 |
Issue | 1 |
Pagination | 91-106 |
Date Published | 2012 Jan |
ISSN | 1558-8238 |
Keywords | Animals, Bone Development, Bone Morphogenetic Protein 2, Bone Morphogenetic Protein 7, Core Binding Factor Alpha 1 Subunit, CREB-Binding Protein, Cyclic AMP Response Element-Binding Protein, Disease Models, Animal, Female, Fetal Therapies, Gene Expression Regulation, Developmental, Humans, Insulin, Insulin-Like Growth Factor I, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Mutant Strains, Mutation, Osteoblasts, Pregnancy, Protein-Serine-Threonine Kinases, Pyruvate Dehydrogenase Acetyl-Transferring Kinase, Recombinant Proteins, Rubinstein-Taybi Syndrome, Signal Transduction, Uterus |
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. |
DOI | 10.1172/JCI59466 |
Alternate Journal | J Clin Invest |
PubMed ID | 22133875 |
Grant List | HD055601 / HD / NICHD NIH HHS / United States |
Related Faculty:
Matthew B. Greenblatt, M.D., Ph.D.