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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.

    Mutations in the coactivator CREB-binding protein (CBP) are a major cause of the human skeletal dysplasia Rubinstein-Taybi syndrome (RTS).  In this paper it is demonstrated that 3-phosphoinositide-dependent kinase 1 (PDK1) is a key regulator of both CBP activity in osteoprogenitor cells and mature osteoblasts and their expression of bone morphogenetic protein 2 (BMP2). Treatment of mice, which have an osteoblast-specific deletion of Pdk1 and are haploinsufficient for Cbp, with BMP partially reversed their RTS phenotype in embryos.  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.


    Shim JH, Greenblatt MB, Singh A, Brady N, Hu D, Drapp R, et al

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