Skeletal Defects in NF1
Our objective is to define the cell of origin responsible for the bowing and recalcitrant bone healing observed in a small proportion of children with NF1, and to identify potential therapeutic targets to prevent this difficult to treat skeletal manifestation of NF1. We have initiated the generation of a series of conditional mutant mice to achieve these goals, and identified the accumulation of pyrophosphate in the ECM of Nf1-/- osteoprogenitors as one mechanism to explain the bowing of the tibia observed in these patients. With a potential target and drug to prevent this bowing and fracture, we are now focusing our efforts to develop tools to identify children with NF1 who will progress to fracture, and to determine if the dystrophic scoliosis observed in 30% of these patients can be explained by similar a mechanism originating from an adjacent neurofibroma or mutated vertebral osteoprogenitors. Another current effort aims at characterizing the poor osteogenic potential of Nf1-/- osteoprogenitors and the impact of these cells in the bone microenvironment.
Influence of Autonomic Nerves on Bone Remodeling, Metastasis and Aging
In this project, we seek to better understand how the autonomic nervous system controls bone remodeling and the physiological and clinical relevance of this pathway. Studies are ongoing to determine if the continued bone loss of the human skeleton after the acquisition of peak bone mass can be explained by changed in the activity of sympathetic and parasympathetic nerves, and how chronic stress can favor the skeletal colonization of metastatic cancer cells.