title: Disruption of the Man-6-P targeting pathway in mice impairs osteoclast secretory lysosome biogenesis.
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.
authors.affiliation: Department of Cell Biology, University Medical Center, Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands.
authors.forename: Eline
authors.initials: E
authors.lastname: van Meel
authors.forename: Marielle
authors.initials: M
authors.lastname: Boonen
authors.forename: Haibo
authors.initials: H
authors.lastname: Zhao
authors.forename: Viola
authors.initials: V
authors.lastname: Oorschot
authors.forename: F Patrick
authors.initials: FP
authors.lastname: Ross
authors.forename: Stuart
authors.initials: S
authors.lastname: Kornfeld
authors.forename: Judith
authors.initials: J
authors.lastname: Klumperman
mesh_terms: D000135:Acid Phosphatase / Q000378:metabolism; D000818:Animals; D002402:Cathepsin D / Q000378:metabolism; D056657:Cathepsin K / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D011992:Endosomes / Q000378:metabolism / Q000648:ultrastructure; D007527:Isoenzymes / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism* / Q000648:ultrastructure; D008264:Macrophages / Q000166:cytology / Q000502:physiology; D008360:Mannosephosphates / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D016253:Microscopy, Immunoelectron; D010010:Osteoclasts / Q000378:metabolism* / Q000648:ultrastructure*; D015398:Signal Transduction / Q000502:physiology; D000071681:Tartrate-Resistant Acid Phosphatase; D017855:Transferases (Other Substituted Phosphate Groups) / Q000235:genetics / Q000378:metabolism; D021601:trans-Golgi Network / Q000378:metabolism / Q000648:ultrastructure
chemical_list: D007527:Isoenzymes; D008360:Mannosephosphates; C027693:mannose-6-phosphate; D017855:Transferases (Other Substituted Phosphate Groups); C548056:GNPTAB protein, mouse; D000135:Acid Phosphatase; C000605511:Acp5 protein, mouse; D000071681:Tartrate-Resistant Acid Phosphatase; D056657:Cathepsin K; D002402:Cathepsin D