Recent clinical studies have reported that individuals with neurofibromatosis type 1 (NF1) are at significant risk for both skeletal and bone abnormalities including osteoporosis -- a disorder in which the bones become porous and brittle; kyphoscoliosis -- an abnormal curvature of the spine; and pseudarthrosis -- an abnormal wound healing of a bone that has fractured. Pseudoarthrosis is a skeletal abnormality that occurs in approximately 3% of young children with NF1. While the incidence is low, this condition is quite debilitating. It results in spontaneous fractures and improper healing of fractures despite repeated surgical procedures over several years. It is a condition that appears, at least in part, to be a consequence of a defect in wound healing. Often, children afflicted with this condition must have limbs amputated and replaced with prostheses in order to walk. This manifestation results in enormous healthcare and socioeconomic costs. Hence, there is a compelling need to find therapies that enhance fracture healing in NF1 patients.

Based on our preliminary studies, previously published work from our lab and others, we hypothesize that the impaired fracture healing process in NF1 is associated with pathologic growth factor production and the downstream effect. We also hypothesize that targeting this specific pathway will improve the fracture healing process for pseudoarthrosis patients. In this application, we have assembled a multi-disciplinary and multi-institutional group of investigators with expertise in skeletal biology, biomedical engineering, signal transduction, and murine models to test our hypothesis.

The studies proposed here will allow us to further test potential therapeutics for the treatment of non-union fracture healing using both genetic murine models and pharmacologic inhibitors. By completing our studies, we will be able to answer whether genetic or pharmacologic targeting of our hypothesized pathway improves fracture healing in a murine model of NF1. These drugs, which are currently in Phase 2 clinical trials for other indications, could be used to treat pseudoarthrosis, and these studies will provide a preclinical trial for the treatment of NF1 patients.