title: 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.
authors.affiliation: 1] Vanderbilt Center for Bone Biology, Vanderbilt University Medical Center, Nashville, Tennessee, USA. [2] Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: Jean
authors.initials: J
authors.lastname: de la Croix Ndong
authors.affiliation: 1] Vanderbilt Center for Bone Biology, Vanderbilt University Medical Center, Nashville, Tennessee, USA. [2] Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee, USA. [3] Department of Orthopaedic Surgery &Rehabilitation, Vanderbilt University Medical Center, Nashville, Tennessee, USA. [4] Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, Tennessee, USA.
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Makowski
authors.affiliation: 1] Vanderbilt Center for Bone Biology, Vanderbilt University Medical Center, Nashville, Tennessee, USA. [2] Department of Orthopaedic Surgery &Rehabilitation, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: Sasidhar
authors.initials: S
authors.lastname: Uppuganti
authors.affiliation: 1] Vanderbilt Center for Bone Biology, Vanderbilt University Medical Center, Nashville, Tennessee, USA. [2] Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Vignaux
authors.affiliation: 1] Vanderbilt Center for Bone Biology, Vanderbilt University Medical Center, Nashville, Tennessee, USA. [2] Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA. [3] Department of Orthopaedics, Nohon Koukan Hospital, Kawasaki, Kanagawa, Japan.
authors.forename: Koichiro
authors.initials: K
authors.lastname: Ono
authors.affiliation: 1] Vanderbilt Center for Bone Biology, Vanderbilt University Medical Center, Nashville, Tennessee, USA. [2] Department of Orthopaedic Surgery &Rehabilitation, Vanderbilt University Medical Center, Nashville, Tennessee, USA. [3] Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, Tennessee, USA. [4] Vanderbilt University Institute of Imaging Sciences, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Perrien
authors.affiliation: Alexion Pharmaceuticals, Cheshire, Connecticut, USA.
authors.forename: Simon
authors.initials: S
authors.lastname: Joubert
authors.affiliation: Laboratory for Orthopedic Pathophysiology and Regenerative Medicine, Istituto Ortopedico Rizzoli, Bologna, Italy.
authors.forename: Serena R
authors.initials: SR
authors.lastname: Baglio
authors.affiliation: Laboratory for Orthopedic Pathophysiology and Regenerative Medicine, Istituto Ortopedico Rizzoli, Bologna, Italy.
authors.forename: Donatella
authors.initials: D
authors.lastname: Granchi
authors.affiliation: Department of Pediatrics, University of Utah, Salt Lake City, Utah, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Stevenson
authors.affiliation: 1] Sarah M. and Charles E. Seay Center for Musculoskeletal Research, Texas Scottish Rite Hospital for Children, Dallas, Texas, USA. [2] Department of Pediatrics, UT Southwestern Medical Center, Dallas, Texas, USA. [3] Eugene McDermott Center for Human Growth &Development, UT Southwestern Medical Center, Dallas, Texas, USA. [4] Department of Orthopaedic Surgery, UT Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Jonathan J
authors.initials: JJ
authors.lastname: Rios
authors.affiliation: 1] Vanderbilt Center for Bone Biology, Vanderbilt University Medical Center, Nashville, Tennessee, USA. [2] Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee, USA. [3] Department of Orthopaedic Surgery &Rehabilitation, Vanderbilt University Medical Center, Nashville, Tennessee, USA. [4] Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, Tennessee, USA.
authors.forename: Jeffry S
authors.initials: JS
authors.lastname: Nyman
authors.affiliation: 1] Vanderbilt Center for Bone Biology, Vanderbilt University Medical Center, Nashville, Tennessee, USA. [2] Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA. [3] Department of Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee, USA. [4] Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: Florent
authors.identifier: 0000000229725633
authors.initials: F
authors.lastname: Elefteriou
mesh_terms: D000293:Adolescent; D000469:Alkaline Phosphatase / Q000096:biosynthesis / Q000627:therapeutic use*; D000818:Animals; D001846:Bone Development / Q000187:drug effects*; D001848:Bone Diseases, Developmental / Q000235:genetics; D055396:Bone Morphogenetic Protein 2 / Q000235:genetics / Q000378:metabolism; D002113:Calcification, Physiologic / Q000187:drug effects*; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D024042:Collagen Type I / Q000096:biosynthesis; D000090602:Collagen Type I, alpha 1 Chain; D024043:Collagen Type II / Q000235:genetics; D011756:Diphosphates / Q000378:metabolism; D004195:Disease Models, Animal; D017886:Durapatite / Q000378:metabolism; D006801:Humans; D007074:Immunoglobulin G / Q000627:therapeutic use*; D007223:Infant; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009456:Neurofibromatosis 1 / Q000188:drug therapy*; D025542:Neurofibromin 1 / Q000235:genetics*; D010006:Osteoblasts / Q000201:enzymology; D010012:Osteogenesis / Q000235:genetics; D028061:Phosphate Transport Proteins / Q000096:biosynthesis / Q000235:genetics; D010727:Phosphoric Diester Hydrolases / Q000096:biosynthesis / Q000235:genetics; D011755:Pyrophosphatases / Q000096:biosynthesis / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use*; D000076182:Sp7 Transcription Factor; D014157:Transcription Factors / Q000235:genetics
chemical_list: C525719:Bmp2 protein, mouse; D055396:Bone Morphogenetic Protein 2; C447413:Col2a1 protein, mouse; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D024043:Collagen Type II; D011756:Diphosphates; D007074:Immunoglobulin G; D025542:Neurofibromin 1; D028061:Phosphate Transport Proteins; D011993:Recombinant Fusion Proteins; D000076182:Sp7 Transcription Factor; C479466:Sp7 protein, mouse; D014157:Transcription Factors; C410982:ank protein, mouse; C107241:diphosphoric acid; D017886:Durapatite; D020928:Mitogen-Activated Protein Kinases; D000469:Alkaline Phosphatase; D010727:Phosphoric Diester Hydrolases; C065962:ectonucleotide pyrophosphatase phosphodiesterase 1; D011755:Pyrophosphatases; C570710:asfotase alfa