Decreased bone formation and increased osteoclastogenesis cause bone loss in mucolipidosis II

Authors

  • Katrin Kollmann,

    1. Department of Biochemistry, Children's Hospital, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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    • These authors contributed equally to this work.
  • Jan Malte Pestka,

    1. Department of Osteology and Biomechanics, Center of Experimental Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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    • These authors contributed equally to this work.
  • Sonja Christin Kühn,

    1. Department of Osteology and Biomechanics, Center of Experimental Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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  • Elisabeth Schöne,

    1. Department of Biochemistry, Children's Hospital, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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  • Michaela Schweizer,

    1. Department of Electron Microscopy, Center for Molecular Neurobiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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  • Kathrin Karkmann,

    1. Department of Biochemistry, Children's Hospital, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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  • Takanobu Otomo,

    1. Department of Biochemistry, Children's Hospital, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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  • Philip Catala-Lehnen,

    1. Department of Osteology and Biomechanics, Center of Experimental Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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  • Antonio Virgilio Failla,

    1. UKE Microscopy Imaging Facility, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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  • Robert Percy Marshall,

    1. Department of Osteology and Biomechanics, Center of Experimental Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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  • Matthias Krause,

    1. Department of Osteology and Biomechanics, Center of Experimental Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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  • Rene Santer,

    1. Department of Biochemistry, Children's Hospital, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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  • Michael Amling,

    1. Department of Osteology and Biomechanics, Center of Experimental Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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  • Thomas Braulke,

    Corresponding author
    1. Department of Biochemistry, Children's Hospital, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
    • Corresponding author: Tel: +49 40 741054493; Fax: +49 40 741058504;

      E-mail: braulke@uke.de

      Corresponding author: Tel: +49 40 741058057; Fax: +49 40 741058010;

      E-mail: schinke@uke.de

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  • Thorsten Schinke

    Corresponding author
    1. Department of Osteology and Biomechanics, Center of Experimental Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
    • Corresponding author: Tel: +49 40 741054493; Fax: +49 40 741058504;

      E-mail: braulke@uke.de

      Corresponding author: Tel: +49 40 741058057; Fax: +49 40 741058010;

      E-mail: schinke@uke.de

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Abstract

Mucolipidosis type II (MLII) is a severe multi-systemic genetic disorder caused by missorting of lysosomal proteins and the subsequent lysosomal storage of undegraded macromolecules. Although affected children develop disabling skeletal abnormalities, their pathogenesis is not understood. Here we report that MLII knock-in mice, recapitulating the human storage disease, are runted with accompanying growth plate widening, low trabecular bone mass and cortical porosity. Intralysosomal deficiency of numerous acid hydrolases results in accumulation of storage material in chondrocytes and osteoblasts, and impaired bone formation. In osteoclasts, no morphological or functional abnormalities are detected whereas osteoclastogenesis is dramatically increased in MLII mice. The high number of osteoclasts in MLII is associated with enhanced osteoblastic expression of the pro-osteoclastogenic cytokine interleukin-6, and pharmacological inhibition of bone resorption prevented the osteoporotic phenotype of MLII mice. Our findings show that progressive bone loss in MLII is due to the presence of dysfunctional osteoblasts combined with excessive osteoclastogenesis. They further underscore the importance of a deep skeletal phenotyping approach for other lysosomal diseases in which bone loss is a prominent feature.

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