Disruption of the Man-6-P Targeting Pathway in Mice Impairs Osteoclast Secretory Lysosome Biogenesis

Authors

  • Eline van Meel,

    1. Department of Cell Biology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands
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    • These authors contributed equally to this work.

  • Marielle Boonen,

    1. Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
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    • These authors contributed equally to this work.

  • Haibo Zhao,

    1. Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
    2. Current address: Center for Osteoporosis and Metabolic Bone Diseases, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
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  • Viola Oorschot,

    1. Department of Cell Biology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands
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  • F. Patrick Ross,

    1. Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
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  • Stuart Kornfeld,

    1. Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
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  • Judith Klumperman

    Corresponding author
    1. Department of Cell Biology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands
      Judith Klumperman, j.klumperman@umcutrecht.nl
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Judith Klumperman, j.klumperman@umcutrecht.nl

Abstract

Osteoclasts are specialized cells that secrete lysosomal acid hydrolases at the site of bone resorption, a process critical for skeletal formation and remodeling. However, the cellular mechanism underlying this secretion and the organization of the endo-lysosomal system of osteoclasts have remained unclear. We report that osteoclasts differentiated in vitro from murine bone marrow macrophages contain two types of lysosomes. The major species is a secretory lysosome containing cathepsin K and tartrate-resistant acid phosphatase (TRAP), two hydrolases critical for bone resorption. These secretory lysosomes are shown to fuse with the plasma membrane, allowing the regulated release of acid hydrolases at the site of bone resorption. The other type of lysosome contains cathepsin D, but little cathepsin K or TRAP. Osteoclasts from Gnptab−/− (gene encoding GlcNAc-1-phosphotransferase α, β-subunits) mice, which lack a functional mannose 6-phosphate (Man-6-P) targeting pathway, show increased secretion of cathepsin K and TRAP and impaired secretory lysosome formation. However, cathepsin D targeting was intact, showing that osteoclasts have a Man-6-P-independent pathway for selected acid hydrolases.

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