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

Jae Hyuck Shim, Matthew B. Greenblatt, Anju Singh, Nicholas Brady, Dorothy Hu, Rebecca Drapp, Wataru Ogawa, Masato Kasuga, Tetsuo Noda, Sang Hwa Yang, Sang Kyou Lee, Vivienne I. Rebel, Laurie H. Glimcher

Research output: Contribution to journalArticle

13 Citations (Scopus)

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 (Pdk1 osx 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 Pdk1 osx 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.

Original languageEnglish
Pages (from-to)91-106
Number of pages16
JournalJournal of Clinical Investigation
Volume122
Issue number1
DOIs
Publication statusPublished - 2012 Jan 3

Fingerprint

CREB-Binding Protein
Bone Morphogenetic Protein 7
Bone Morphogenetic Protein 2
3-Phosphoinositide-Dependent Protein Kinases
Osteoblasts
Rubinstein-Taybi Syndrome
Mutation
Osteogenesis
Intercellular Signaling Peptides and Proteins
Transcription Factors
Embryonic Structures
Parturition
Phenotype
Rubinstein Taybi like syndrome

All Science Journal Classification (ASJC) codes

  • Medicine(all)

Cite this

Shim, Jae Hyuck ; Greenblatt, Matthew B. ; Singh, Anju ; Brady, Nicholas ; Hu, Dorothy ; Drapp, Rebecca ; Ogawa, Wataru ; Kasuga, Masato ; Noda, Tetsuo ; Yang, Sang Hwa ; Lee, Sang Kyou ; Rebel, Vivienne I. ; Glimcher, Laurie H. / Administration of BMP2/7 in utero partially reverses Rubinstein-Taybi syndrome-like skeletal defects induced by Pdk1 or Cbp mutations in mice. In: Journal of Clinical Investigation. 2012 ; Vol. 122, No. 1. pp. 91-106.
@article{5f37606f001c4538bd6fc66de5781f68,
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 (Pdk1 osx 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 Pdk1 osx 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.",
author = "Shim, {Jae Hyuck} and Greenblatt, {Matthew B.} and Anju Singh and Nicholas Brady and Dorothy Hu and Rebecca Drapp and Wataru Ogawa and Masato Kasuga and Tetsuo Noda and Yang, {Sang Hwa} and Lee, {Sang Kyou} and Rebel, {Vivienne I.} and Glimcher, {Laurie H.}",
year = "2012",
month = "1",
day = "3",
doi = "10.1172/JCI59466",
language = "English",
volume = "122",
pages = "91--106",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "1",

}

Shim, JH, Greenblatt, MB, Singh, A, Brady, N, Hu, D, Drapp, R, Ogawa, W, Kasuga, M, Noda, T, Yang, SH, Lee, SK, Rebel, VI & Glimcher, LH 2012, 'Administration of BMP2/7 in utero partially reverses Rubinstein-Taybi syndrome-like skeletal defects induced by Pdk1 or Cbp mutations in mice', Journal of Clinical Investigation, vol. 122, no. 1, pp. 91-106. https://doi.org/10.1172/JCI59466

Administration of BMP2/7 in utero partially reverses Rubinstein-Taybi syndrome-like skeletal defects induced by Pdk1 or Cbp mutations in mice. / Shim, Jae Hyuck; Greenblatt, Matthew B.; Singh, Anju; Brady, Nicholas; Hu, Dorothy; Drapp, Rebecca; Ogawa, Wataru; Kasuga, Masato; Noda, Tetsuo; Yang, Sang Hwa; Lee, Sang Kyou; Rebel, Vivienne I.; Glimcher, Laurie H.

In: Journal of Clinical Investigation, Vol. 122, No. 1, 03.01.2012, p. 91-106.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Administration of BMP2/7 in utero partially reverses Rubinstein-Taybi syndrome-like skeletal defects induced by Pdk1 or Cbp mutations in mice

AU - Shim, Jae Hyuck

AU - Greenblatt, Matthew B.

AU - Singh, Anju

AU - Brady, Nicholas

AU - Hu, Dorothy

AU - Drapp, Rebecca

AU - Ogawa, Wataru

AU - Kasuga, Masato

AU - Noda, Tetsuo

AU - Yang, Sang Hwa

AU - Lee, Sang Kyou

AU - Rebel, Vivienne I.

AU - Glimcher, Laurie H.

PY - 2012/1/3

Y1 - 2012/1/3

N2 - 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 (Pdk1 osx 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 Pdk1 osx 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.

AB - 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 (Pdk1 osx 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 Pdk1 osx 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.

UR - http://www.scopus.com/inward/record.url?scp=84855464261&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84855464261&partnerID=8YFLogxK

U2 - 10.1172/JCI59466

DO - 10.1172/JCI59466

M3 - Article

VL - 122

SP - 91

EP - 106

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

SN - 0021-9738

IS - 1

ER -