Administration of BMP2/7 in utero partially reverses Rubinstein-Taybi syndrome-like skeletal defects induced by Pdk1 or Cbp mutations in mice.
Administration of BMP2/7 in utero partially reverses Rubinstein-Taybi syndrome-like skeletal defects induced by Pdk1 or Cbp mutations in mice.
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DOI：
10.1172/jci59466
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发表时间：
2012-01
期刊：
影响因子：
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通讯作者：
Jae-hyuck Shim;M. Greenblatt;Anju Singh;N. Brady;D. Hu;R. Drapp;W. Ogawa;M. Kasuga;T. Noda;Sang-Hwa Yang;Sang-Kyou Lee;V. I. Rebel;L. Glimcher
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文献类型：
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作者：
Jae-hyuck Shim;M. Greenblatt;Anju Singh;N. Brady;D. Hu;R. Drapp;W. Ogawa;M. Kasuga;T. Noda;Sang-Hwa Yang;Sang-Kyou Lee;V. I. Rebel;L. Glimcher
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.
