β-Catenin modulation in neurofibromatosis type 1 bone repair: therapeutic implications.

Published

Journal Article

Tibial pseudarthrosis causes substantial morbidity in patients with neurofibromatosis type 1 (NF1). We studied tibial pseudarthrosis tissue from patients with NF1 and found elevated levels of β-catenin compared to unaffected bone. To elucidate the role of β-catenin in fracture healing, we used a surgically induced tibial fracture model in conditional knockout (KO) Nfl (Nf1(flox/flox)) mice. When treated with a Cre-expressing adenovirus (Ad-Cre), there was a localized knockdown of Nf1 in the healing fracture and a subsequent development of a fibrous pseudarthrosis. Consistent with human data, elevated β-catenin levels were found in the murine fracture sites. The increased fibrous tissue at the fracture site was rescued by local treatment with a Wingless-type MMTV integration site (Wnt) antagonist, Dickkopf-1 (Dkk1). The murine pseudarthrosis phenotype was also rescued by conditional β-catenin gene inactivation. The number of colony-forming unit osteoblasts (CFU-Os), a surrogate marker of undifferentiated mesenchymal cells able to differentiate to osteoblasts, correlated with the capacity to form bone at the fracture site. Our findings indicate that the protein level of β-catenin must be precisely regulated for normal osteoblast differentiation. An up-regulation of β-catenin in NF1 causes a shift away from osteoblastic differentiation resulting in a pseudarthrosis in vivo These results support the notion that pharmacological modulation of β-catenin can be used to treat pseudarthrosis in patients with NF1.-Ghadakzadeh, S., Kannu, P., Whetstone, H., Howard A., Alman, B. A. β-catenin modulation in neurofibromatosis type 1 bone repair: therapeutic implications.

Full Text

Duke Authors

Cited Authors

  • Ghadakzadeh, S; Kannu, P; Whetstone, H; Howard, A; Alman, BA

Published Date

  • September 2016

Published In

Volume / Issue

  • 30 / 9

Start / End Page

  • 3227 - 3237

PubMed ID

  • 27306335

Pubmed Central ID

  • 27306335

Electronic International Standard Serial Number (EISSN)

  • 1530-6860

International Standard Serial Number (ISSN)

  • 0892-6638

Digital Object Identifier (DOI)

  • 10.1096/fj.201500190rr

Language

  • eng