Orthopedic & Muscular System: Current Research
Open Access

The skeletal phenotype in neurofibromatosis type 1-structural defects, molecular mechanisms and therapeutic approaches

6^th Annual Surgeons & Orthopedics Conference & Expo

September 12-14, 2016 Atlanta, USA

Jirko Kuhnisch

Charit�© - University Medicine Berlin, Germany
Experimental and Clinical Research Center, Germany
Max-Delbr�¼ck-Centrum for Molecular Medicine, Germany

Posters & Accepted Abstracts: Orthop Muscular Syst

Abstract :

Patients with Neurofibromatosis Type 1 (NF1) develop subcutaneous benign tumors and dysfunction of multiple organs. About 30% of NF1 patients are affected by skeletal signs such as osteopenia, kyphoscoliosis, tibia bowing, or pseudarthrosis of the tibia. NF1 is caused by autosomal dominant mutation of the NF1 gene encoding the protein neurofibromin a regulator of the MAPK/ERK pathway. During the last decade we and others elucidated for the NF1 associated skeletal phenotype the molecular mechanisms, structural defects and explored therapeutic approaches by using tissue specific knockout mice and patient samples. In Nf1-Prx1 and Nf1-Col1 mice we demonstrated that loss of neurofibromin leads to multiscale defects in cortical bone i) increased marco-porosity, ii) increased micro-porosity (osteocyte lacunae), iii) diminished mineralization, and iv) reduced organic matrix maturation. This overall weakens the mechanical strength of bone tissue in long bones significantly. In NF1 patients this may result in fractures and pseudarthrosis. Inhibition of the MAPK/ERK pathway with Lovastatin, Trametinib, PD0325901 and Selumetinib normalized bone healing in neurofibromin knockout mouse models. Downregulation of the MAPK/ERK pathway restored normal osteoblast differentiation/function and sufficiently prevented accumulation of fibroblasts within the bone fracture site. In a recent breakthrough study, Asfotase-�± replacing alkaline phosphatase (ALP) function specifically in bone tissue, was used to restore normal bone mass in Nf1-Osx1 knock-out mice. In summary, neurofibromin controls development of the skeletal system by regulating the MAPK/ERK pathway in chondrocytes, pre-osteoblasts, osteoblasts, and osteocytes. Therapeutic approaches normalizing MAPK/ERK and ALP activity promise future therapeutic inventions for NF1 patients.

Biography :

Email: jirko.kuehnisch@gmx.de