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

Nat Med. 2014 Aug;20(8):904-10. doi: 10.1038/nm.3583. Epub 2014 Jul 6.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

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

Substances

  • Bmp2 protein, mouse
  • Bone Morphogenetic Protein 2
  • Col2a1 protein, mouse
  • Collagen Type I
  • Collagen Type II
  • Diphosphates
  • Immunoglobulin G
  • Neurofibromin 1
  • Phosphate Transport Proteins
  • Recombinant Fusion Proteins
  • Sp7 Transcription Factor
  • Sp7 protein, mouse
  • Transcription Factors
  • ank protein, mouse
  • collagen type I, alpha 1 chain
  • diphosphoric acid
  • Durapatite
  • Mitogen-Activated Protein Kinases
  • Alkaline Phosphatase
  • Phosphoric Diester Hydrolases
  • ectonucleotide pyrophosphatase phosphodiesterase 1
  • Pyrophosphatases
  • asfotase alfa