Year: 2014
Type: dissertation
Abstract: Skeletal abnormalities occur in half of the individuals with neurofibromatosis type-1 (NF1), the most difficult to manage is congenital pseudarthrosis of tibia (CPT). High levels of β-catenin result in a phenotype similar to CPT in mice fractures. β -catenin in CPT samples was up-regulated, therefore we hypothesized that Wnt/ β-catenin pathway partially mediates the effect of NF1 mutation on bone by altering the differentiation of MSCs into osteoblasts. Conditional knock-out Nf1 mice were crossed with conditional β-catenin over-expressing and knock-out models. Adenovirus expressing Cre recombinase was injected at the fracture site to activate the conditional alleles. Fracture healing was evaluated by radiological, histological and biomechanical tests. Nf1 deficient tibial fractures were associated with higher cellular β-catenin levels and delayed healing, exhibiting a fibro-cartilaginous phenotype with abundant undifferentiated MSCs. Down-regulating and stabilizing β-catenin, improved and exacerbated Nf1 deficient fracture healing respectively. These data indicate that the level of β-catenin in NF1 patients and Nf1 deficient fractures is abnormally elevated, and this level inhibits osteoblastogenesis and bone repair. Since pharmacologic agents to inhibit β-catenin are under developemt, this data also suggests a novel therapeutic approach to improve bone healing in patients with NF1.
Source: TSpace (University of Toronto)
Author: Saber Ghadakzadeh
Language: English
Subfield: Clinical Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W3161039895