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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, … , Vivienne I. Rebel, Laurie H. Glimcher
Jae-Hyuck Shim, … , Vivienne I. Rebel, Laurie H. Glimcher
Published December 1, 2011
Citation Information: J Clin Invest. 2012;122(1):91-106. https://doi.org/10.1172/JCI59466.
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Research Article Bone Biology

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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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

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

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Figure 1

Abnormal skeletogenesis in PDK1-deficient mice.

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Abnormal skeletogenesis in PDK1-deficient mice.
(A) Ossification of P2 P...
(A) Ossification of P2 Pdk1fl/fl and Pdk1osx skulls was analyzed by μCT. Arrowheads indicate the nasal bone. (B) Alizarin Red/Alcian Blue–stained skeletal preps demonstrating calvarial hypomineralization and clavicular hypoplasia in P2 Pdk1osx mice. Arrows indicate the zygomatic bone (top). Hematoxylin and eosin–stained longitudinal section of the femur in P2 Pdk1fl/fl and Pdk1osx mice (middle). Pdk1osx mice display low bone mass and spontaneous fractures (bottom). Original magnification, ×40. (C and D) Alizarin Red/Alcian Blue–stained skeletal preps of the indicated mice.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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