RANKL subcellular trafficking and regulatory mechanisms in osteocytes

ABSTRACT The receptor activator of the NF‐κB ligand (RANKL) is the central player in the regulation of osteoclastogenesis, and the quantity of RANKL presented to osteoclast precursors is an important factor determining the magnitude of osteoclast formation. Because osteoblastic cells are thought to...

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Bibliographic Details
Published in:Journal of bone and mineral research 2013-09, Vol.28 (9), p.1936-1949
Main Authors: Honma, Masashi, Ikebuchi, Yuki, Kariya, Yoshiaki, Hayashi, Madoka, Hayashi, Naoki, Aoki, Shigeki, Suzuki, Hiroshi
Format: Article
Language:English
Subjects:
Animals
Bone Marrow Cells - cytology
Bone Marrow Cells - drug effects
Bone Marrow Cells - metabolism
Cell Communication - drug effects
Cell Culture Techniques
Cell Membrane - drug effects
Cell Membrane - metabolism
Collagen - pharmacology
Dendrites - drug effects
Dendrites - metabolism
Immune system
Lysosomes - drug effects
Lysosomes - metabolism
Macrophages - cytology
Macrophages - drug effects
Mice
Mice, Inbred C57BL
Models, Biological
OPG
OSTEOCLASTOGENESIS
Osteoclasts - cytology
Osteoclasts - drug effects
Osteoclasts - metabolism
OSTEOCYTE
Osteocytes - cytology
Osteocytes - drug effects
Osteocytes - metabolism
Osteogenesis - drug effects
Osteoprotegerin - metabolism
Porosity
Protein Transport - drug effects
RANK Ligand - metabolism
RANKL
Regulation
Rodents
Subcellular Fractions - drug effects
Subcellular Fractions - metabolism
SUBCELLULAR TRAFFIC
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Summary:ABSTRACT The receptor activator of the NF‐κB ligand (RANKL) is the central player in the regulation of osteoclastogenesis, and the quantity of RANKL presented to osteoclast precursors is an important factor determining the magnitude of osteoclast formation. Because osteoblastic cells are thought to be a major source of RANKL, the regulatory mechanisms of RANKL subcellular trafficking have been studied in osteoblastic cells. However, recent reports showed that osteocytes are a major source of RANKL presentation to osteoclast precursors, prompting a need to reinvestigate RANKL subcellular trafficking in osteocytes. Investigation of molecular mechanisms in detail needs well‐designed in vitro experimental systems. Thus, we developed a novel co‐culture system of osteoclast precursors and osteocytes embedded in collagen gel. Experiments using this model revealed that osteocytic RANKL is provided as a membrane‐bound form to osteoclast precursors through osteocyte dendritic processes and that the contribution of soluble RANKL to the osteoclastogenesis supported by osteocytes is minor. Moreover, the regulation of RANKL subcellular trafficking, such as OPG‐mediated transport of newly synthesized RANKL molecules to lysosomal storage compartments, and the release of RANKL to the cell surface upon stimulation with RANK are confirmed to be functional in osteocytes. These results provide a novel understanding of the regulation of osteoclastogenesis.
ISSN:0884-0431
1523-4681
DOI:10.1002/jbmr.1941