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

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 (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.

SUBMITTER: de la Croix Ndong J

PROVIDER: S-EPMC4126855 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

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

de la Croix Ndong Jean J Makowski Alexander J AJ Uppuganti Sasidhar S Vignaux Guillaume G Ono Koichiro K Perrien Daniel S DS Joubert Simon S Baglio Serena R SR Granchi Donatella D Stevenson David A DA Rios Jonathan J JJ Nyman Jeffry S JS Elefteriou Florent F

Nature medicine 20140706 8

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 ...[more]

PMID: 24997609

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Dataset Information

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

Publications

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

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