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