Pathogenesis of congenital tibial bowing and pseudarthrosis in neurofibromatosis type 1.

Neurofibromatosis type 1 (NF1) is a genetic condition characterized by multiple café-au-lait spots, freckling and benign nodules of peripheral nerves. Five percent of NF1-children present with bowing of the lower leg. Progressive bowing ultimately results in a pathological fracture with pseudarthrosis (false joint) development, due to impaired healing. The mechanism of bowing and pseudarthrosis formation in NF1 is poorly understood and the success rate of current treatments is limited, leading frequently to amputation of the lower leg and foot. Recent studies suggest that both copies of the NF1 gene are inactivated in NF1-related pseudarthrosis tissue, therefore we aim to further unravel the genetic, cellular and molecular mechanisms underlying this manifestation. The role of acquired mutations in the NF1 gene in specific bone cells and effect on periosteum (outer membrane that covers bone)-derived cells will be studied, using special Nf1 mice (Nf1 expression regulated in skeleton) and human NF1-related pseudarthrosis samples. We will investigate the potential of a cell-based therapy to improve bone healing in a Nf1-pseudarthrosis mouse model using an implant seeded with normal functioning periosteal cells. New insights into the process of bone healing in NF1-related pseudarthrosis tissue hopefully will contribute to the development of efficient cell-based therapeutic modalities.

Keywords:Neurofibromatosis type 1, Periosteum, Cell based therapy, Pseudarthrosis, Congenital bowing tibia, NF1

Disciplines:Laboratory medicine, Palliative care and end-of-life care, Regenerative medicine, Other basic sciences, Other health sciences, Nursing, Other paramedical sciences, Other translational sciences, Other medical and health sciences