Neurofibromatosis type-1 (NF1) can present with focal skeletal dysplasias that remain extremely difficult to treat. Elefteriou and colleagues report that ablation of Nf1 in bone-forming cells results in accumulation of pyrophosphate (PPi), a strong inhibitor of hydroxyapatite formation, and that a chronic extracellular signal–regulated kinase (ERK)-dependent increase in expression of genes promoting PPi 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 (ALP) and PPi breakdown, further contributing to PPi accumulation. The short stature and impaired bone mineralization in mice lacking Nf1 in osteochondroprogenitors or osteoblasts can be corrected by asfotase-alpha, a recombinant form of ALP used in hypophosphatasia. This study highlights the role of neurofibromin as an important regulator of bone mineralization and suggests that altered PPi homeostasis contributes to the skeletal dysplasia related to NF1 and that some of the NF1 skeletal manifestations could be prevented pharmacologically.
Posted by Nicola Brunetti-Pierri, MD