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

de la Croix Ndong J, Makowski AJ, Uppuganti S, Vignaux G, Ono K, Perrien DS, Joubert S, Baglio SR, Granchi D, Stevenson DA, Rios JJ, Nyman JS, Elefteriou F
Nat Med. 2014 20 (8): 904-10

PMID: 24997609 · PMCID: PMC4126855 · DOI:10.1038/nm.3583

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 (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 and PPi breakdown, further contributing to PPi 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 PPi concentration. These results establish neurofibromin as an essential regulator of bone mineralization. They also suggest that altered PPi homeostasis contributes to the skeletal dysplasias associated with NF1 and that some of the NF1 skeletal conditions could be prevented pharmacologically.

MeSH Terms (32)

Adolescent Alkaline Phosphatase Animals Bone Development Bone Diseases, Developmental Bone Morphogenetic Protein 2 Calcification, Physiologic Cells, Cultured Child Child, Preschool Collagen Type I Collagen Type II Diphosphates Disease Models, Animal Durapatite Humans Immunoglobulin G Infant Mice Mice, Inbred C57BL Mice, Knockout Mitogen-Activated Protein Kinases Neurofibromatosis 1 Neurofibromin 1 Osteoblasts Osteogenesis Phosphate Transport Proteins Phosphoric Diester Hydrolases Pyrophosphatases Recombinant Fusion Proteins Sp7 Transcription Factor Transcription Factors

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