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Cited by 560Bone Metabolism and DiseasesBone health and osteoporosis researchOsteomyelitis and Bone Disorders Research

Coupling of bone resorption and formation by RANKL reverse signalling

Ikebuchi, Yuki, Aoki, Shigeki, Honma, Masashi, Hayashi, Madoka, Sugamori, Yasutaka, Khan, Masud, Kariya, Yoshiaki, Kato, Genki +5 more·2018·Nature
DOI 10.1038/s41586-018-0482-7
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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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Crossref · 10.1038/s41586-018-0482-7

Cites

34 of 34 references verified0 citation errors · 0 not checkable

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  • Vesicular RANK binds to RANKL on the osteoblast surface and triggers mTOR-dependent stimulation of Runx2.

    “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]

  • Actively resorbing osteoclasts promote differentiation of neighboring osteoblast precursors into mature bone-forming cells.

    “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]

  • RANKL monomers expressed on osteoblasts are not activated by RANK or by OPG, as indicated by deletion of RANK or OPG failing to reduce bone formation.

    “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]

  • Osteoblasts do not efficiently deposit bone ECM when RANKL reverse signaling is suppressed.

    “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]

  • RANKL clustering on early osteoblasts may be required for activation of RANKL reverse signaling in resorption lacunae.

    “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]

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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
Publisher
Springer Science and Business Media LLC
Published
2018-09-05
Volume
561
Issue
7722
Pages
195-200
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/s41586-018-0482-7
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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