Does Spinal Neurofibroma-Derived Pyrophosphate Contribute to NF1 Dystrophic Scoliosis?
Abstract
Using genetic tools and preclinical mouse models, several laboratories have contributed over the last 10 years to a better understanding of the skeletal conditions associated with NF1. What we learned is that NF1 non-bone union following fracture (pseudarthrosis) in children with NF1 has likely an origin in a restricted pool of tibial osteoprogenitors that cannot differentiate into bone-forming (and repairing) osteoblasts, and in osteoclasts, the bone-resorbing cells, that are too sensitive to signals promoting their differentiation and activity. Based on these data, numerous efforts have been made to design treatments that could promote bone healing and bone union. Our understanding of the cause of the spinal deformities that affect some children with NF1, compared to these studies, lags behind. Sharp angulation of the vertebral column in these children requires repeated and invasive surgeries, and there is no therapy to prevent or limit progression to this condition. One of our latest breakthroughs is the discovery that neurofibromin is a necessary protein for normal mineralization of the skeleton, whose role in osteoblasts is to limit the generation of pyrophosphate (PPi), a strong inhibitor of bone mineralization. This role explains why poorly mineralized bone tissues have been observed in human NF1 pseudarthrosis biopsies and in all the mouse models of NF1 pseudarthrosis. But most importantly, normal mineralization is required for optimal mechanical resistance of the skeleton and bone healing. Hence, these data suggest that tibia bowing, fracture, and recalcitrant bone repair in NF1 are caused, at least in part, by improper mineralization of the skeleton. The identification of excess pyrophosphate as the molecular cause of this mineralization defect in NF1, which appears to be conserved from mouse models to humans, led us to the demonstration that pyrophosphate hydrolysis by targeted enzyme therapy based on the use of Asfotase alpha, could be a promising therapy in NF1 to prevent tibia bowing and fracture. In this application, we propose to test the hypothesis that excess PPi generated by cells with NF1 inactivating mutations is not limited to osteoblasts, but may occur also in NF1-deficient Schwann cells in paraspinal neurofibroma tumors. Sharp angulation scoliosis in children with NF1 is indeed often associated with the presence of paraspinal tumors and therefore the existence of an "osteolytic" factor (destroying bone) has been postulated. However, the nature of this factor has never been characterized. We postulate that this factor is in fact PPi, which is not an osteolytic factor but a molecule inhibiting normal bone mineralization, which could be ectopically released by Schwann cells of the vertebral adjacent neurofibroma, and progressively impair vertebral mineralization, bone strength and repair, and eventually vertebral shape, leading to the sharp angulated vertebral axis seen in 10%-30% of children with NF1. We will test this hypothesis by analyzing the vertebral axis of NF1 mouse models known to have paraspinal neurofibromas, shared by Dr. Y. Zhu and Dr. N. Ratner. We will look for signs of defective bone mineralization, shape and repair, and isolate Schwann cells from paraspinal tumors of these mice to determine if the molecular changes leading to ectopic and supraphysiologic levels of PPi in osteoblasts also exist in Nf1-deficient Schwann cells. The major potential impact of this work lies in the availability of a drug able to get rid of the excess PPi generated by NF1-deficient cells. This drug, named Asfotase alpha, is a recombinant modified form of alkaline phosphatase, whose activity is to hydrolyse PPi. Asfotase alpha has an IgG moiety to increase its half-life (hence less injections required) and a stretch of 10 aspartic residues that augment its selectivity for bone tissues. It is already used clinically for the treatment of children born lacking alkaline phosphatase (i.e.,
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510525
Entities
People
- Florent Elefteriou
Organizations
- Baylor College of Medicine
- United States Army