Asfotase-α improves bone growth, mineralization and strength in mouse models of neurofibromatosis type-1

Individuals with neurofibromatosis type-1 (NF1) can manifest focal skeletal dysplasias that remain extremely difficult to treat. NF1 is caused by mutations in the NF1 gene, which encodes the RAS GTPase-activating protein neurofibromin. We report here that ablation of Nf1 in bone-forming cells leads to supraphysiologic accumulation of pyrophosphate (PP i), a strong inhibitor of hydroxyapatite formation, and that a chronic extracellular signal-regulated kinase (ERK)-dependent increase in expression of genes promoting PP i synthesis and extracellular transport, namely Enpp1 and Ank, causes this phenotype. Nf1 ablation also prevents bone morphogenic protein-2-induced osteoprogenitor differentiation and, consequently, expression of alkaline phosphatase and PP i breakdown, further contributing to PP i accumulation. The short stature and impaired bone mineralization and strength in mice lacking Nf1 in osteochondroprogenitors or osteoblasts can be corrected by asfotase- α enzyme therapy aimed at reducing PP i concentration. These results establish neurofibromin as an essential regulator of bone mineralization. They also suggest that altered PP i homeostasis contributes to the skeletal dysplasias associated with NF1 and that some of the NF1 skeletal conditions could be prevented pharmacologically

Aberrant Myeloid Differentiation Contributes to the Development of Osteoporosis in Neurofibromatosis Type 1

Neurofibromatosis type 1 (NF1), also known as von Recklinghausen disease, is a common autosomal dominant genetic disorder affecting approximately 1 in 3000 individuals worldwide. NF1 results from heritable or spontaneous mutations of the NF1 tumor suppressor gene. NF1 encodes the protein neurofibromin, which functions to negatively regulate Ras-activity. Approximately 50 % of NF1 patients develop osteopenia or osteoporosis, resulting in significantly increased rates of long-bone fracture and morbidity. While defective osteoblast bone anabolism has been implicated as a central factor in the pathogenesis of NF1 associated skeletal deficits, recent data suggest that NF1 (Nf1) haploinsufficiency within the hematopoietic compartment, particularly in osteoclasts and myeloid progenitors, plays a pivotal role in engendering NF1 osseous manifestations. In this chapter, we review the latest data from clinical studies and murine models delineating a critical role for hematopoietic compartment, myeloid progenitors of NF1 (Nf1) haploinsufficient and their progeny-osteoclasts, in the pathogenesis of NF1 associated osteopenia/osteoporosis and discuss putative targets for future therapeutics