Disruption of the Man‐6‐P Targeting Pathway in Mice Impairs Osteoclast Secretory Lysosome Biogenesis
Open Access
- 5 April 2011
- Vol. 12 (7), 912-924
- https://doi.org/10.1111/j.1600-0854.2011.01203.x
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.Keywords
This publication has 63 references indexed in Scilit:
- Vacuolization of mucolipidosis type II mouse exocrine gland cells represents accumulation of autolysosomesMolecular Biology of the Cell, 2011
- Mice Lacking Mannose 6-Phosphate Uncovering Enzyme Activity Have a Milder Phenotype than Mice Deficient forN-Acetylglucosamine-1-Phosphotransferase ActivityMolecular Biology of the Cell, 2009
- Comparative Pathology of Murine Mucolipidosis Types II and IIICVeterinary Pathology, 2009
- Acid phosphatase 5 is responsible for removing the mannose 6-phosphate recognition marker from lysosomal proteinsProceedings of the National Academy of Sciences, 2008
- Sortilin mediates the lysosomal targeting of cathepsins D and HBiochemical and Biophysical Research Communications, 2008
- Synaptotagmin VII Regulates Bone Remodeling by Modulating Osteoclast and Osteoblast SecretionDevelopmental Cell, 2008
- Imaging and imagination: understanding the endo-lysosomal systemHistochemistry and Cell Biology, 2008
- Intracellular membrane trafficking in bone resorbing osteoclastsMicroscopy Research and Technique, 2003
- Localization of cathepsin K in human osteoclasts by in situ hybridization and immunohistochemistryBone, 1997
- Polarized secretion of lysosomal enzymes: co-distribution of cation-independent mannose-6-phosphate receptors and lysosomal enzymes along the osteoclast exocytic pathway.The Journal of cell biology, 1988