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

Nature Medicine volume 20, pages 904910 (2014) | Download Citation

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  • A Corrigendum to this article was published on 07 April 2015

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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.

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Change history

  • 13 March 2015

     In the version of this article initially published, the acknowledgment that Daniel S. Perrien was supported by a Career Development Award from the US Department of Veterans Affairs was omitted. The error has been corrected in the HTML and PDF versions of the article.

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Acknowledgements

We thank A. Bianchi and F. Cailotto for their help in establishing the PPi measurement protocol and K.S. Campbell for editorial assistance. This work was supported by a Young Investigator Award (2012–01–028) from the Children's Tumor Foundation (J.d.l.C.N.), the US National Institute of Arthritis and Musculoskeletal and Skin Diseases and National Center for Research Resources, part of the US National Institutes of Health, under award numbers 5R01 AR055966 (F.E.) and S10 RR027631 (D.S.P.), the National Center for Advancing Translational Sciences of the National Institutes of Health under award number UL1TR001105 (J.J.R.), the Pediatric Orthopaedic Society of North America and Texas Scottish Rite Hospital for Children (J.J.R.), a Career Development Award (no. 1IK2BX001634) from the US Department of Veterans Affairs, Biomedical Laboratory Research and Development Program (D.S.P), and the US Army Medical Research Acquisition Activity under award W81XWH–11–1–0250 (D.A.S.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the US National Institutes of Health or US government.

Author information

Affiliations

  1. Vanderbilt Center for Bone Biology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.

    • Jean de la Croix Ndong
    • , Alexander J Makowski
    • , Sasidhar Uppuganti
    • , Guillaume Vignaux
    • , Koichiro Ono
    • , Daniel S Perrien
    • , Jeffry S Nyman
    •  & Florent Elefteriou
  2. Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.

    • Jean de la Croix Ndong
    • , Guillaume Vignaux
    • , Koichiro Ono
    •  & Florent Elefteriou
  3. Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee, USA.

    • Alexander J Makowski
    •  & Jeffry S Nyman
  4. Department of Orthopaedic Surgery & Rehabilitation, Vanderbilt University Medical Center, Nashville, Tennessee, USA.

    • Alexander J Makowski
    • , Sasidhar Uppuganti
    • , Daniel S Perrien
    •  & Jeffry S Nyman
  5. Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, Tennessee, USA.

    • Alexander J Makowski
    • , Daniel S Perrien
    •  & Jeffry S Nyman
  6. Department of Orthopaedics, Nohon Koukan Hospital, Kawasaki, Kanagawa, Japan.

    • Koichiro Ono
  7. Vanderbilt University Institute of Imaging Sciences, Vanderbilt University Medical Center, Nashville, Tennessee, USA.

    • Daniel S Perrien
  8. Alexion Pharmaceuticals, Cheshire, Connecticut, USA.

    • Simon Joubert
  9. Laboratory for Orthopedic Pathophysiology and Regenerative Medicine, Istituto Ortopedico Rizzoli, Bologna, Italy.

    • Serena R Baglio
    •  & Donatella Granchi
  10. Department of Pediatrics, University of Utah, Salt Lake City, Utah, USA.

    • David A Stevenson
  11. Sarah M. and Charles E. Seay Center for Musculoskeletal Research, Texas Scottish Rite Hospital for Children, Dallas, Texas, USA.

    • Jonathan J Rios
  12. Department of Pediatrics, UT Southwestern Medical Center, Dallas, Texas, USA.

    • Jonathan J Rios
  13. Eugene McDermott Center for Human Growth & Development, UT Southwestern Medical Center, Dallas, Texas, USA.

    • Jonathan J Rios
  14. Department of Orthopaedic Surgery, UT Southwestern Medical Center, Dallas, Texas, USA.

    • Jonathan J Rios
  15. Department of Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.

    • Florent Elefteriou
  16. Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.

    • Florent Elefteriou

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Contributions

F.E. and J.d.l.C.N. designed the study; J.d.l.C.N., A.J.M., S.U., G.V., K.O., J.J.R., D.A.S., S.R.B., D.G., J.S.N. performed experiments; J.d.l.C.N., D.S.P., J.S.N. and F.E. collected and analyzed data; S.J. provided reagents; F.E. and J.d.l.C.N. wrote the manuscript.

Competing interests

D.A.S. has received honoraria from Alexion for consultation on hypophosphatasia.

Corresponding author

Correspondence to Florent Elefteriou.

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https://doi.org/10.1038/nm.3583

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