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

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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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Figure 1: Uncontrolled Ank, Enpp1 and Spp1 expression and increased PPi production in Nf1-deficient osteoblasts.
Figure 2: Altered PPi homeostasis in Nf1-deficient chondrocytes.
Figure 3: Blunted BMP2 response and osteoblast differentiation potential in Nf1-deficient osteoprogenitors.
Figure 4: BMP2 does not promote differentiation in Nf1-deficient BMSCs but exacerbates their mineralization deficit.
Figure 5: sALP-FcD10 improves bone growth and cortical bone parameters in growing Col2-Nf1 KO mice.
Figure 6: sALP-FcD10 improves trabecular bone mass, mineralization and bone structure in Osx-Nf1 KO mice.

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.

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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.

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Correspondence to Florent Elefteriou.

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

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de la Croix Ndong, J., Makowski, A., Uppuganti, S. et al. Asfotase-α improves bone growth, mineralization and strength in mouse models of neurofibromatosis type-1. Nat Med 20, 904–910 (2014). https://doi.org/10.1038/nm.3583

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