BoneKEy Reports | BoneKEy Watch
Potential therapy for Rubinstein-Taybi syndrome
DOI:10.1038/bonekey.2012.30
Rubinstein-Taybi syndrome is a human skeletal dysplasia that results from mutations in the coactivator CREB-binding protein (CBP). Shim et al. conducted studies in mice demonstrating that CBP activity is regulated by 3-phosphoinositide-dependent kinase 1 (PDK1) and uncovered the insulin signaling pathway that occurs in osteoprogenitor cells and mature osteoblasts, and that regulates osteoblast activity.
This involves PDK1-mediated downregulation of TWIST2, which then leads to increased expression of RUNX2 and an increase in bone morphogenetic protein 2 (BMP2) levels. This leads to enhanced bone formation and a rise in glucose metabolism.
This pathway was shown to occur in vivo in mouse embryos, and those that were knockouts for either CBP or PDK1 developed skeletal abnormalities. Treatment of both types of embryo with recombinant human BMP2 resulted in partial reversal of the skeletal abnormalities present at birth, suggesting growth factor supplementation in utero warrants investigation. This provides a potential therapy for Rubinstein-Taybi syndrome and possibly other hereditary skeletal dysplasias.
Editor's comment: Despite demonstrations that embryonic developmental defects can be corrected by supplementation of relevant growth factors, recent advances in our understanding of the genetics of nearly all skeletal dysplasias have failed to lead to the development of therapeutic approaches. This is the first proof-of-principle that demonstrates that direct replacement of a growth factor that is downstream of the mutated gene could be a promising therapeutic approach.
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