RANKL subcellular trafficking and regulatory mechanisms in osteocytes
Open accessAbstract
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.
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In a 3D collagen scaffold coculture, primary osteocytes supported osteoclast formation, but the efficiency decreased with a decrease in the pore size of the membrane; large pore membranes allowed osteocyte dendrites to touch osteoclast precursors through the pores, but this contact was not observed with small-pore membranes.
“In another in vitro study, primary osteocytes were cocultured on a 3D collagen scaffold with osteoclast precursors separated by a porous membrane. Again, the osteocytes supported osteoclast formation, but the efficiency of their effect decreased with a decrease in the pore size of the membrane. Confocal microscopy showed that large pore membranes allow osteocyte dendrites to touch osteoclast”
From Bone remodeling: an operational process ensuring survival and bone mechanical competence (2022) · cites this paper as [57]
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- Authors
- Honma, M., Ikebuchi, Y., Kariya, Y., Hayashi, M., Hayashi, N., Aoki, S., & Suzuki, H.
- Affiliations
- University of Tokyo Hospital (JP)
- Corresponding author
- Honma, Masashi
- Venue
- Journal of Bone and Mineral Research
- Publisher
- Oxford University Press (OUP)
- Published
- 2013-03-25
- Volume
- 28
- Issue
- 9
- Pages
- 1936-1949
- ISSN
- 0884-0431 (ISSN-L)
- 1523-4681
- OpenAlex
- W1799961617
- Cited by
- 98
- References
- 36
- Citations by year
- 2026: 4 · 2025: 1 · 2024: 6 · 2023: 9 · 2022: 5 · 2021: 6 · 2020: 14 · 2019: 13 · 2018: 6 · 2017: 6 · 2016: 6 · 2015: 9 · 2014: 8 · 2013: 5
- FWCI
- 4.18
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
- Locations
- Journal of Bone and Mineral Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Japan Society for the Promotion of Science (24890048, 22136015)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
- Health Sciences › Medicine › Rheumatology › Bone and Dental Protein Studies
- Health Sciences › Medicine › Rheumatology › Osteomyelitis and Bone Disorders Research
- Keywords
- RANKL, osteocytes, intracellular trafficking, osteoclastogenesis, osteoclast precursors, co-culture model, collagen gel, soluble RANKL, osteoprotegerin, lysosomal storage, RANK signaling, bone remodeling
- MeSH terms
- Animals, Bone Marrow Cells, Cell Communication, Cell Membrane, Collagen, Dendrites, Lysosomes, Macrophages, Mice, Inbred C57BL, Models, Biological, Osteoclasts, Osteocytes, Osteogenesis, Subcellular Fractions, Porosity, Cell Culture Techniques, Protein Transport, Mice, Osteoprotegerin, RANK Ligand
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