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

Jean De La Croix Ndong, Alexander J. Makowski, Sasidhar Uppuganti, Guillaume Vignaux, Koichiro Ono, Daniel S. Perrien, Simon Joubert, Serena R. Baglio, Donatella Granchi, David A. Stevenson, Jonathan J. Rios, Jeffry S. Nyman, Florent Elefteriou

Research output: Contribution to journalArticlepeer-review

55 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)904-910
Number of pages7
JournalNature medicine
Volume20
Issue number8
DOIs
StatePublished - Aug 2014

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology

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