Discovery of Novel Drugs To Improve Bone Health in Neurofibromatosis Type 1: The Wnt/Beta-Catenin Pathway in Fracture Repair and Pseudarthrosis
Annual rept. 1 June 2013 - 31 May 2014
HOSPITAL FOR SICK CHILDREN TORONTO (ONTARIO)
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Patients with Neurofibromatosis NF1 exhibit deficient bone healing The cause of poor bone healing in NF1 is unclear, and pharmacologic approaches to improve bone repair are lacking. Beta-catenin is a protein that regulates osteoblasts during bone healing. When beta-catenin protein level is high, it prevents osteoblast differentiation, and undifferentiated fibroblast-like cells persist at the fracture site, resulting in a pseudarthrosis. Genetically engineered mice in which the Nf1 gene can be deleted when cells are exposed to Cre-Recombinase were studied. An adenovirus expressing Cre-Recombinase was injected to the fracture site to knock out the gene. Mice in which the beta-catenin gene can be knocked out by exposure to Cre-Recombinase were used to decrease beta-catenin during fracture repair. An open tibial fracture, fixed with an intramedullar pin, was used to study fracture healing. Five to ten mice were studied in each group at each time point, and fracture repair assessed at three and six weeks using radiology and histology. Beta-catenin protein level during fracture repair in mice lacking the Nf1 gene measured five times higher than normal. Mice lacking Nf1 gene showed deficient fracture repair. In contrast, mice lacking Nf1 gene, but that also express a low level of beta-catenin healed their tibia fracture quicker and with more bone as measured using both radiographic and histologic parameters. This work so far shows that beta-catenin protein is elevated during fracture repair in mice lacking Nf1. Inhibition of beta-catenin can improve the quality of the bone repair process.
- Anatomy and Physiology
- Medicine and Medical Research