title: Administration of BMP2/7 in utero partially reverses Rubinstein-Taybi syndrome-like skeletal defects induced by Pdk1 or Cbp mutations in mice.
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.
authors: Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts, USA. jshim@hsph.harvard.edu
authors: Jae-Hyuck
authors: JH
authors: Shim
authors: Matthew B
authors: MB
authors: Greenblatt
authors: Anju
authors: A
authors: Singh
authors: Nicholas
authors: N
authors: Brady
authors: Dorothy
authors: D
authors: Hu
authors: Rebecca
authors: R
authors: Drapp
authors: Wataru
authors: W
authors: Ogawa
authors: Masato
authors: M
authors: Kasuga
authors: Tetsuo
authors: T
authors: Noda
authors: Sang-Hwa
authors: SH
authors: Yang
authors: Sang-Kyou
authors: SK
authors: Lee
authors: Vivienne I
authors: VI
authors: Rebel
authors: Laurie H
authors: LH
authors: Glimcher
mesh_terms: D000818:Animals; D001846:Bone Development / Q000235:genetics / Q000502:physiology; D055396:Bone Morphogenetic Protein 2 / Q000008:administration & dosage* / Q000235:genetics; D055419:Bone Morphogenetic Protein 7 / Q000008:administration & dosage*; D050882:CREB-Binding Protein / Q000172:deficiency / Q000235:genetics*; D050659:Core Binding Factor Alpha 1 Subunit / Q000172:deficiency / Q000235:genetics; D017362:Cyclic AMP Response Element-Binding Protein / Q000172:deficiency / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D046128:Fetal Therapies / Q000379:methods*; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D007328:Insulin / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D009154:Mutation; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011247:Pregnancy; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D011994:Recombinant Proteins / Q000008:administration & dosage; D012415:Rubinstein-Taybi Syndrome / Q000196:embryology / Q000235:genetics* / Q000378:metabolism / Q000628:therapy*; D015398:Signal Transduction; D014599:Uterus
chemical_list: C525718:BMP2 protein, human; C525819:BMP7 protein, human; C525719:Bmp2 protein, mouse; D055396:Bone Morphogenetic Protein 2; D055419:Bone Morphogenetic Protein 7; D050659:Core Binding Factor Alpha 1 Subunit; C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D007328:Insulin; C000631429:PDK1 protein, human; C000631433:Pdk1 protein, mouse; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D011994:Recombinant Proteins; C493716:Runx2 protein, mouse; D007334:Insulin-Like Growth Factor I; D050882:CREB-Binding Protein; C494364:Crebbp protein, mouse; D017346:Protein Serine-Threonine Kinases