Multiple increased osteoclast functions in individuals with neurofibromatosis type 1

Authors

  • David A. Stevenson,

    1. Department of Pediatrics, Division of Medical Genetics, University of Utah, Salt Lake City, Utah
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  • Jincheng Yan,

    1. Third Hospital, Hebei Medical University, Shijiazhuang, China
    2. Departments of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana
    3. Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana
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  • Yongzheng He,

    1. Departments of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana
    2. Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana
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  • Huijie Li,

    1. Third Hospital, Hebei Medical University, Shijiazhuang, China
    2. Departments of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana
    3. Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana
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  • Yaling Liu,

    1. Third Hospital, Hebei Medical University, Shijiazhuang, China
    2. Departments of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana
    3. Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana
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  • Qi Zhang,

    1. Third Hospital, Hebei Medical University, Shijiazhuang, China
    2. Departments of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana
    3. Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana
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  • Yongmin Jing,

    1. Third Hospital, Hebei Medical University, Shijiazhuang, China
    2. Departments of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana
    3. Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana
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  • Zhiping Guo,

    1. Third Hospital, Hebei Medical University, Shijiazhuang, China
    2. Departments of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana
    3. Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana
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  • Wei Zhang,

    1. Third Hospital, Hebei Medical University, Shijiazhuang, China
    2. Departments of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana
    3. Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana
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  • Dalong Yang,

    1. Third Hospital, Hebei Medical University, Shijiazhuang, China
    2. Departments of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana
    3. Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana
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  • Xiaohua Wu,

    1. Departments of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana
    2. Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana
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  • Heather Hanson,

    1. Department of Pediatrics, Division of Medical Genetics, University of Utah, Salt Lake City, Utah
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  • Xiaohong Li,

    1. Departments of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana
    2. Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana
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  • Karl Staser,

    1. Departments of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana
    2. Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana
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  • David H. Viskochil,

    1. Department of Pediatrics, Division of Medical Genetics, University of Utah, Salt Lake City, Utah
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  • John C. Carey,

    1. Department of Pediatrics, Division of Medical Genetics, University of Utah, Salt Lake City, Utah
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  • Shi Chen,

    1. Departments of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana
    2. Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana
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  • Lucy Miller,

    1. Departments of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana
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  • Kent Roberson,

    1. Departments of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana
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  • Laurie Moyer-Mileur,

    1. Department of Pediatrics, Division of Medical Genetics, University of Utah, Salt Lake City, Utah
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  • Menggang Yu,

    1. Biostatistics, Indiana University School of Medicine, Indianapolis, Indiana
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  • Elisabeth L. Schwarz,

    1. ARUP Institute for Clinical and Experimental Pathology, Salt Lake City, Utah
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  • Marzia Pasquali,

    1. Department of Pathology, University of Utah, Salt Lake City, Utah
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  • Feng-Chun Yang

    Corresponding author
    1. Departments of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana
    2. Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana
    3. Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, Indiana
    • Indiana University School of Medicine, Cancer Research Institute, 1044 W. Walnut St., R4/427, Indianapolis, IN 46202.
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  • How to Cite this Article: Stevenson DA, Yan J, He Y, Li H, Liu Y, Zhang Q, Jing Y, Guo Z, Zhang W, Yang D, Wu X, Hanson H, Li X, Staser K, Viskochil DH, Carey JC, Chen S, Miller L, Roberson K, Moyer-Mileur L, Yu M, Schwarz EL, Pasquali M, Yang F-C. 2011. Multiple increased osteoclast functions in individuals with neurofibromatosis type 1. Am J Med Genet Part A 155:1050–1059.

  • David A. Stevenson and Jincheng Yan contributed equally to this work.

Abstract

Skeletal abnormalities including scoliosis, tibial dysplasia, sphenoid wing dysplasia, and decreased bone mineral density (BMD) are associated with neurofibromatosis type 1 (NF1). We report the cellular phenotype of NF1 human-derived osteoclasts and compare the in vitro findings with the clinical phenotype. Functional characteristics (e.g., osteoclast formation, migration, adhesion, resorptive capacity) and cellular mechanistic alterations (e.g., F-actin polymerization, MAPK phosphorylation, RhoGTPase activity) from osteoclasts cultured from peripheral blood of individuals with NF1 (N = 75) were assessed. Osteoclast formation was compared to phenotypic, radiologic, and biochemical data. NF1 osteoprogenitor cells demonstrated increased osteoclast forming capacity. Human NF1-derived osteoclasts demonstrated increased migration, adhesion, and in vitro bone resorption. These activities coincided with increased actin belt formation and hyperactivity in MAPK and RhoGTPase pathways. Although osteoclast formation was increased, no direct correlation of osteoclast formation with BMD, markers of bone resorption, or the clinical skeletal phenotype was observed suggesting that osteoclast formation in vitro cannot directly predict NF1 skeletal phenotypes. While NF1 haploinsufficiency produces a generalized osteoclast gain-in-function and may contribute to increased bone resorption, reduced BMD, and focal skeletal defects associated with NF1, additional and perhaps local modifiers are likely required for the development of skeletal abnormalities in NF1. © 2011 Wiley-Liss, Inc.

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