Cellular Origin of Bone Manifestations in Neurofibromatosis Type 1
Abstract
Neurofibromatosis type 1 (NF1) is an autosomal dominant disease due to mutations in the NF1 tumor suppressor gene. NF1 patients can be affected by a variety of symptoms with a wide range of severity, including cutaneous, neurological, orthopedic and malignant manifestations. Bone manifestations in NF1 affect approximately 50% of patients and comprise osteoporosis, bone dysplasia, pseudarthrosis, cranial anomalies and spine deformities. Scoliosis is the most common osseous defect associated with NF1 as 20% of NF1 patients have a disorder of the spine. Non-dystrophic deformity can be managed similarly to idiopathic scoliosis with expert examination and bracing. However, dystrophic scoliosis associated with vertebral and rib anomalies, often requires surgical fusion with instrumentation and bone grafting. Long bone dysplasia affects 5% of NF1 patients but can lead to congenital pseudarthrosis of the tibia (CPT) a very severe pathology. Treating CPT is very challenging for orthopaedic surgeons and requires complex surgical procedures including fixation, bone grafting, periosteum grafting and induced membrane techniques. The efficacy of these various treatments is still not demonstrated and risk of amputation remains high. To improve the clinical care of NF1 patients a better understanding of underlying genetic bases and mechanisms of NF1 pathophysiology is needed. NF1 patients carry a heterozygote inactivating mutation in the NF1 gene. The NF1 gene has been described as bearing one of the highest mutation rates in the human genome. Research on the genetic bases of neurofibromas (NFBs) and café-au-lait macules (CALMs) revealed that somatic mutations in specific cell types, i.e., Schwann cells and melanocytes respectively, occur in these localized NF1 lesions causing the loss of the second NF1 allele. However, for bone lesions, the cell types carrying a potential mutation in the second NF1 allele have not been determined. The goal of this project is to characterize which cell types are affected in bone manifestations in NF1 in human and in a clinically relevant mouse model. We will study the role of a specific cell population derived from the neural crest during embryonic development that give rise to Schwann cells and melanocytes in the skin. Inactivation of both NF1 alleles in these cells causes cutaneous and plexiform NFBs, as well as CALMs and other NF1 symptoms in mice. Our preliminary evaluations also show bone anomalies reminiscent of NF1 symptoms and indicates that the same neural crest derivatives producing Schwann cells and skeletal stem/progenitor cells in bone may be the cell of origin of bone manifestations. This animal model is unique as it is the first model to recapitulate several aspects of the NF1 disease and may serve as a valuable pre-clinical model. We therefore propose to perform an advance characterization of the cell types responsible for the bone anomalies in this mouse model and how NF1 gene inactivation impacts their functions. In parallel, we will analyze bone samples from NF1 patients affected by congenital pseudarthrosis of the tibia and dystrophic scoliosis. This patient population requires complex surgical procedures to correct the bone anomalies. Bone samples collected during these surgical procedures will be analyzed to identify the cell types carrying inactivation of NF1 gene. The strength and novelty of this project is to combine the analyses of a clinically relevant animal model and patient samples to elucidate the mechanisms of NF1 bone manifestations and identify potential common mechanisms between tumor and non-tumor NF1 manifestations. In the long term, deciphering the cell type of origin of bone lesions and the molecular pathways affected by NF1 mutation will help design new pharmacological and cellular approaches to treat bone manifestations in NF1.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310359
Entities
People
- Celine Colnot
Organizations
- French National Institute of Health and Medical Research
- United States Army