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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 2

Characterization of osteoprogenitors and gene expression in Pdk1osx mice.

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Characterization of osteoprogenitors and gene expression in Pdk1osx mice...
(A) Representative FACS profiles on pregated, live CD45–Ter119– lineage cells harvested from long bones of E17.5 Pdk1fl/fl and Pdk1dm1 embryos. Percentages represent the percentage of cells within that quadrant. Values are mean ± SD of biologic replicates. (B) Sections from the sagittal suture of P2 Pdk1fl/fl and Pdk1osx neonates analyzed for the expression of Opn by in situ hybridization. Original magnification, ×100. The osteogenic front (OF) and sutural mesenchyme (SM) are labeled. (C) Total RNA was extracted from calvaria of P2 Pdk1fl/fl and Pdk1osx mice, and osteoblast gene expression was analyzed by quantitative PCR. The value of each sample, each from a different mouse, is indicated with a circle, and the average value of each group indicated with a red line.
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