ROLE OF NEUROFIBROMIN GENE IN SKELETON DEVELOPMENT, GROWTH, REMODELING AND REPAIR
NEUROFIBROMATOSIS (NF1) is characterized by a large spectrum of clinical manifestations, mostly of neurocutaneous nature, but also by skeletal maladies that affect various bone elements. These defects can be categorized as generalized (low BMD, low vitamin D level, increased resorption) and focal (tibia bowing, pseudoarthrosis, dystrophic scoliosis). NF1 is caused by mutations in the NF1 gene. The current major school of thoughts is that patients inherit a single allele of non-mutated NF1, whose function is lost somatically and focally in specific tissues, giving rise to the various manifestations characteristic of NF1. Whether this mechanism contributes to the bony NF1 defects is unknown. By the use of a mutant mouse models lacking Nf1 in various bone cells, we are dissecting the role of Nf1 during the different phases of bone development, growth, remodeling and fracture repair. We have previously shown using mice that lack Nf1 in osteoblasts only (Nf1ob-/- mice) that Nf1 regulates collagen synthesis, ECM mineralization and bone resorption (PMID: 17141628). This study also revealed that Rankl and ATF4 are targets of neurofibromin signaling in osteoblasts, and that protein diet manipulations can correct skeletal displasiae in mouse models characterized by ATF4 dysfunction, including the Nf1ob-/- mice. Our current interest is to compare mouse models lacking Nf1 in mesenchymal cells, chondrocytes or osteoblasts for their developmental bone characteristics and for their ability to repair bone fracture.
These mouse models are used for understanding the role of Nf1 in the mesenchymal lineage but are also evaluated for their value as pre-clinical mouse models. Based on the characterization of the molecular pathway regulated by Nf1 in osteoblasts, which involve RAS, ERK, RSK2 and ATF4, we showed that pharmacological inhibition of RAS signaling by local delivery of lovastatin can improve bone healing in our Nf1 mouse models (PMID: 20200958). This work is funded by the NIH (P.I. Dr. F. Elefteriou) and the Children’s Tumor Foundation (Young Investigator Award fellowship to Dr. J. Ndong.
|Weixi Wang||Jean Ndong||Matthew Karolak|