The DOI matches its Crossref record; 34 of the 35 references it cites were found in a registry or an index.
Coupling of bone resorption and formation by RANKL reverse signalling
Abstract
Receptor activator of nuclear factor-kappa B (RANK) ligand (RANKL) binds RANK on the surface of osteoclast precursors to trigger osteoclastogenesis. Recent studies have indicated that osteocytic RANKL has an important role in osteoclastogenesis during bone remodelling; however, the role of osteoblastic RANKL remains unclear. Here we show that vesicular RANK, which is secreted from the maturing osteoclasts, binds osteoblastic RANKL and promotes bone formation by triggering RANKL reverse signalling, which activates Runt-related transcription factor 2 (Runx2). The proline-rich motif in the RANKL cytoplasmic tail is required for reverse signalling, and a RANKL(Pro29Ala) point mutation reduces activation of the reverse signalling pathway. The coupling of bone resorption and formation is disrupted in RANKL(Pro29Ala) mutant mice, indicating that osteoblastic RANKL functions as a coupling signal acceptor that recognizes vesicular RANK. RANKL reverse signalling is therefore a potential pharmacological target for avoiding the reduced bone formation associated with inhibition of osteoclastogenesis.
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In the citing paper
“However, a recent study demonstrated that vesicular RANK binds to RANKL on the osteoblast surface (and possibly on osteocytes) and triggers the mTOR-dependent stimulation of Runx2238 (Fig. 5).”
From Bone remodeling: an operational process ensuring survival and bone mechanical competence (2022) · cites this paper as [238]
In the citing paper
“This finding suggests a previously unknown scenario in which actively resorbing osteoclasts promote the differentiation of neighboring osteoblast precursors into mature bone-forming cells.”
From Bone remodeling: an operational process ensuring survival and bone mechanical competence (2022) · cites this paper as [238]
In the citing paper
“RANKL monomers expressed on osteoblasts are not activated by RANK238 or by OPG, as indicated by the deletion of RANK or OPG failing to reduce bone formation.245”
From Bone remodeling: an operational process ensuring survival and bone mechanical competence (2022) · cites this paper as [238]
In the citing paper
“The physiological importance of the messages shuttled by EVs has been confirmed by the observation that osteoblasts do not efficiently deposit bone ECM when RANKL reverse signaling is suppressed.238”
From Bone remodeling: an operational process ensuring survival and bone mechanical competence (2022) · cites this paper as [238]
In the citing paper
“RANKL clustering on early osteoblasts may therefore be required for the activation of RANKL reverse signaling in resorption lacunae, similar to the effect of shuttling RANK in osteoclast EVs during bone remodeling (Fig. 5) or that of an anti-RANKL antibody-containing leucine zippers, which induce trimer formation.238”
From Bone remodeling: an operational process ensuring survival and bone mechanical competence (2022) · cites this paper as [238]
In the citing paper
“Osteosarcoma tumours arise during puberty, when many progenitor cells undergo differentiation in response to signalling via, for example, FGF2 (ref.96 ), RANKL 96,97 and IGF1 (ref.98 ).”
From Osteosarcoma (2022) · cites this paper as [97]
Citations
Cites
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Osteoblast-Osteoclast Communication and Bone Homeostasis
Kim, J., Lin, C., Stavre, Z., Greenblatt, M. B., & Shim, J. (2020) · Cells · doi:10.3390/cells9092073 · Cited by 1,266
Osteoclast differentiation by RANKL and OPG signaling pathways
Udagawa, N., Koide, M., Nakamura, M., Nakamichi, Y., Yamashita, T., Uehara, S., Kobayashi, Y., Furuya, Y., Yasuda, H., Fukuda, C., et al. (2020) · Journal of Bone and Mineral Metabolism · doi:10.1007/s00774-020-01162-6 · Cited by 765
Self-citationBeird, H. C., Bielack, S. S., Flanagan, A. M., Gill, J., Heymann, D., Janeway, K. A., Livingston, J. A., Roberts, R. D., Strauss, S. J., & Gorlick, R. (2022) · Nature Reviews Disease Primers · doi:10.1038/s41572-022-00409-y · Cited by 660
RANKL biology: bone metabolism, the immune system, and beyond
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Metadata
- Authors
- Ikebuchi, Y., Aoki, S., Honma, M., Hayashi, M., Sugamori, Y., Khan, M., Kariya, Y., Kato, G., Tabata, Y., Penninger, J. M., Udagawa, N., Aoki, K., & Suzuki, H.
- Affiliations
- University of Tokyo Hospital (JP)
- Tokyo Medical and Dental University (JP)
- Kyoto University (JP)
- Institute of Molecular Biotechnology (AT)
- Matsumoto Dental University (JP)
- Corresponding author
- Honma, Masashi
- ORCID
- Venue
- Nature
- Published
- 2018-09-05
- Volume
- 561
- Issue
- 7722
- Pages
- 195-200
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2890611509
- Cited by
- 557
- References
- 35
- Citations by year
- 2026: 37 · 2025: 71 · 2024: 85 · 2023: 63 · 2022: 75 · 2021: 78 · 2020: 83 · 2019: 53 · 2018: 12
- FWCI
- 20.10
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Japan Society for the Promotion of Science (17K19776, 16K11818, 18H02918, 16H05445, 17F17124, 18K04734, 16K20419, 16H06261, 16H05508)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
- Health Sciences › Medicine › Orthopedics and Sports Medicine › Bone health and osteoporosis research
- Health Sciences › Medicine › Rheumatology › Osteomyelitis and Bone Disorders Research
- Keywords
- RANK, osteoclasts, osteoblasts, bone resorption, bone formation, bone remodeling, Runx2, proline-rich motif, osteoclastogenesis
- MeSH terms
- Animals, Bone Resorption, Cell Differentiation, Cross-Linking Reagents, Female, Male, Mice, Inbred C57BL, Osteoblasts, Osteoclasts, Osteogenesis, Signal Transduction, Amino Acid Substitution, Cytoplasmic Vesicles, Core Binding Factor Alpha 1 Subunit, Mice, RANK Ligand, Receptor Activator of Nuclear Factor-kappa B
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