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 (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.

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

All Science Journal Classification (ASJC) codes

  • Medicine(all)

Fingerprint Dive into the research topics of 'Administration of BMP2/7 in utero partially reverses Rubinstein-Taybi syndrome-like skeletal defects induced by Pdk1 or Cbp mutations in mice'. Together they form a unique fingerprint.

  • Cite this

    Shim, J. H., Greenblatt, M. B., Singh, A., Brady, N., Hu, D., Drapp, R., Ogawa, W., Kasuga, M., Noda, T., Yang, S. H., Lee, S. K., Rebel, V. I., & Glimcher, L. H. (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, 122(1), 91-106. https://doi.org/10.1172/JCI59466