Human apolipoprotein E isoforms differentially affect bone mass and turnover in vivo

Authors

  • Marco Dieckmann,

    1. Department of Molecular Genetics, University of Texas Southwestern, Dallas, TX, USA
    Search for more papers by this author
  • F Timo Beil,

    1. Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
    2. Department of Orthopaedics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
    Search for more papers by this author
  • Brigitte Mueller,

    1. Department of Orthopaedics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
    2. Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
    Search for more papers by this author
  • Alexander Bartelt,

    1. Department of Orthopaedics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
    2. Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
    Search for more papers by this author
  • Robert P Marshall,

    1. Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
    Search for more papers by this author
  • Till Koehne,

    1. Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
    Search for more papers by this author
  • Michael Amling,

    1. Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
    Search for more papers by this author
  • Wolfgang Ruether,

    1. Department of Orthopaedics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
    Search for more papers by this author
  • Jackie A Cooper,

    1. Cardiovascular Genetics, BHF Laboratories, Institute of Cardiovascular Sciences, Faculty of Population Health Sciences University College London, London, UK
    Search for more papers by this author
  • Steve E Humphries,

    1. Cardiovascular Genetics, BHF Laboratories, Institute of Cardiovascular Sciences, Faculty of Population Health Sciences University College London, London, UK
    Search for more papers by this author
  • Joachim Herz,

    1. Department of Molecular Genetics, University of Texas Southwestern, Dallas, TX, USA
    2. Department of Neuroscience, University of Texas Southwestern, Dallas, TX, USA
    3. Department of Neurology and Neurotherapeutics, University of Texas Southwestern, Dallas, TX, USA
    4. Centre for Neurosciences, University of Freiburg, Germany
    Search for more papers by this author
  • Andreas Niemeier

    Corresponding author
    1. Department of Orthopaedics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
    2. Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
    • Department of Orthopaedics and Department Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, D - 20246 Hamburg, Germany.
    Search for more papers by this author

  • For a Commentary on this article, please see Ralston (J Bone Miner Res. 2012:28:234-235. DOI: 10.1002/jbmr.1840).

Abstract

The primary role of apolipoprotein E (apoE) is to mediate the cellular uptake of lipoproteins. However, a new role for apoE as a regulator of bone metabolism in mice has recently been established. In contrast to mice, the human APOE gene is characterized by three common isoforms APOE ε2, ε3, and ε4 that result in different metabolic properties of the apoE isoforms, but it remains controversial whether the APOE polymorphism influences bone traits in humans. To clarify this, we investigated bone phenotypes of apoE knock-in (k.i.) mice, which express one human isoform each (apoE2 k.i., apoE3 k.i., apoE4 k.i.) in place of the mouse apoE. Analysis of 12-week-old female k.i. mice revealed increased levels of biochemical bone formation and resorption markers in apoE2 k.i. animals as compared to apoE3 k.i. and apoE4 k.i., with a reduced osteoprotegerin (OPG)/receptor activator of NF-κB ligand (RANKL) ratio in apoE2 k.i., indicating increased turnover with prevailing resorption in apoE2 k.i. Accordingly, histomorphometric and micro–computed tomography (µCT) analyses demonstrated significantly lower trabecular bone mass in apoE2 than in apoE3 and apoE4 k.i. animals, which was reflected by a significant reduction of lumbar vertebrae maximum force resistance. Unlike trabecular bone, femoral cortical thickness, and stability was not differentially affected by the apoE isoforms. To extend these observations to the human situation, plasma from middle-aged healthy men homozygous for ε2/ε2, ε3/ε3, and ε4/ε4 (n = 21, n = 80, n = 55, respectively) was analyzed with regard to bone turnover markers. In analogy to apoE2 k.i. mice, a lower OPG/RANKL ratio was observed in the serum of ε2/ε2 carriers as compared to ε3/ε3 and ε4/ε4 individuals (p = 0.02 for ε2/ε2 versus ε4/ε4). In conclusion, the current data strongly underline the general importance of apoE as a regulator of bone metabolism and identifies the APOE ε2 allele as a potential genetic risk factor for low trabecular bone mass and vertebral fractures in humans. © 2013 American Society for Bone and Mineral Research

Ancillary