Neurofibromatosis type 1 (NF1) is a common autosomal dominant genetic disorder that is caused by mutations in the NF1 tumor suppressor gene, which functions as a GTPase activating protein (GAP) for Ras. Patients with NF1 have a range of malignant and nonmalignant manifestations such as cutaneous and plexiform neurofibromas. Many laboratories focusing on the studies understand the pathogenesis of the peripheral and central nervous system tumors that affect a wide range of NF1 patients. However, less effort to date has been focused on understanding the molecular mechanisms underlying the pathogenesis of many of the non-malignant manifestations of NF1, particularly the skeletal manifestations that affect up to 50% of all NF1 patients. Recent clinical studies have found that individuals with NF1 are at significant risk for both generalized osteoporotic and focal skeletal abnormalities including kyphoscoliosis and pseudoarthrosis. The most prevalent focal skeletal sequela in NF1 is kyphoscoliosis, which affects 35% of NF1 patients. Kyphoscoliosis is a collective term for pathological curvature of the spine. Kyphoscoliosis begins in young school age children, is profoundly deforming, and frequently requires multiple surgeries to limit the lifelong morbidities including restrictive lung disease, pain, and disfigurement. Pseudoarthrosis is a third skeletal abnormality that occurs in approximately 3% of young children with NF1. This condition presents as a spontaneous fracture, particularly in tibia. Though the incidence of this disorder is low, pseudoarthrosis is nonetheless a profoundly debilitating condition that appears at least in part to be a consequence of a defect in wound healing. Children afflicted with this condition have a failure of bone union despite repeated surgical procedures over several years to repair these spontaneous fractures. Oftentimes the only way to enable these children with persistent fractures to walk is to perform an amputation of the affected limb and provide a prosthesis.

The health costs and sequelae of osteoporosis in the general population are well reported in both the lay press and in scientific literature. Given that osteoporosis is being detected in young children with NF1 and in young women, the ultimate health costs and sequelae of this abnormality per individual in NF1 patients may be significantly greater. Moreover, the health costs of the surgeries alone for kyphoscoliosis can amount to hundreds of thousands of dollars for each individual.

In this application, we have assembled a multidisciplinary and multi-institutional group of investigators with expertise in skeletal biology, biomedical engineering, signal transduction, murine models, and translational human protocols to evaluate the role of neurofibromin in skeletal remodeling and bone strength in murine models. We have generated the first model to our knowledge that appears to have kyphoscoliosis and osteoporosis. Studies to be conducted here will characterize the cellular and molecular mechanisms underlying the osseous manifestations of NF1.

These studies will provide insights as to the role of neurofibromin in osteoporosis, kyphoscoliosis, fractures, and fracture healing as well as skeletal strength. Studies are also proposed to evaluate a specific molecular target that could be useful in treating and, at least in concept, in preventing bone manifestations. Finally, the proposal also provides a unique opportunity to conduct parallel noninvasive studies in the patients with NF1 to evaluate similar basic processes. If our hypotheses are correct, there are drugs that are being developed for other purposes that could be redirected to treat the skeletal dysplasias.