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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“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
Ceramide Triggers Budding of Exosome Vesicles into Multivesicular Endosomes
Trajković, K., Hsu, C., Chiantia, S., Rajendran, L., Wenzel, D., Wieland, F., Schwille, P., Brügger, B., & Simons, M. (2008) · Science · doi:10.1126/science.1153124 · Cited by 3,760
2016 update of the PRIDE database and its related tools
Vizcaíno, J. A., Csordás, A., del‐Toro, N., Dianes, J. A., Griss, J., Lavidas, I., Mayer, G., Pérez‐Riverol, Y., Reisinger, F., Ternent, T., et al. (2015) · Nucleic Acids Research · doi:10.1093/nar/gkv1145 · Cited by 3,440
OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph node organogenesis.
Kong, Y.-Y., Yoshida, H., Sarosi, I., Tan, H.-L., Timms, E., Capparelli, C., Morony, S., Oliveira-dos-Santos, A. J., Van, G., Itie, A., et al. (1999) · Nature · doi:10.1038/16852 · Cited by 3,351
Self-citationDempster, D. W., Compston, J. E., Drezner, M. K., Glorieux, F. H., Kanis, J. A., Malluche, H., Meunier, P. J., Ott, S. M., Recker, R. R., & Parfitt, A. M. (2013) · Journal of Bone and Mineral Research · doi:10.1002/jbmr.1805 · Cited by 2,543
Suda, T., Takahashi, N., Udagawa, N., Jimi, E., Gillespie, M. T., & Martin, T. J. (1999) · Endocrine Reviews · doi:10.1210/edrv.20.3.0367 · Cited by 2,345
Self-citationBiology of Bone Tissue: Structure, Function, and Factors That Influence Bone Cells
Florencio-Silva, R., Sasso, G. R. D. S., Sasso-Cerri, E., Simões, M. J., & Cerri, P. S. (2015) · BioMed Research International · doi:10.1155/2015/421746 · Cited by 2,044
Evidence for osteocyte regulation of bone homeostasis through RANKL expression
Nakashima, T., Hayashi, M., Fukunaga, T., Kurata, K., Oh-hora, M., Feng, J. Q., Bonewald, L. F., Kodama, T., Wutz, A., Wagner, E. F., et al. (2011) · Nature Medicine · doi:10.1038/nm.2452 · Cited by 1,778
Self-citationMatrix-embedded cells control osteoclast formation
Xiong, J., Onal, M., Jilka, R. L., Weinstein, R. S., Manolagas, S. C., & O'Brien, C. A. (2011) · Nature Medicine · doi:10.1038/nm.2448 · Cited by 1,304
EV-TRACK: transparent reporting and centralizing knowledge in extracellular vesicle research
EV-TRACK Consortium, Van Deun, J., Mestdagh, P., Agostinis, P., Akay, Ö., Anand, S., Anckaert, J., Martinez, Z. A., Baetens, T., Beghein, E., et al. (2017) · Nature Methods · doi:10.1038/nmeth.4185 · Cited by 1,284
Regulation of osteoblast differentiation by transcription factors
Komori, T. (2006) · Journal of Cellular Biochemistry · doi:10.1002/jcb.20958 · Cited by 1,027
Sims, N. A., & Martin, T. J. (2014) · BoneKEy Reports · doi:10.1038/bonekey.2013.215 · Cited by 745
Saksela, K., Cheng, G., & Baltimore, D. (1995) · The EMBO Journal · doi:10.1002/j.1460-2075.1995.tb07024.x · Cited by 559
Pederson, L., Ruan, M., Westendorf, J. J., Khosla, S., & Oursler, M. J. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0805133106 · Cited by 556
Suppression of bone formation by osteoclastic expression of semaphorin 4D
Negishi-Koga, T., Shinohara, M., Komatsu, N., Bito, H., Kodama, T., Friedel, R. H., & Takayanagi, H. (2011) · Nature Medicine · doi:10.1038/nm.2489 · Cited by 498
Design and Use of a Phage Display Library
Pini, A., Viti, F., Santucci, A., Carnemolla, B., Zardi, L., Neri, P., & Neri, D. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.34.21769 · Cited by 423
Boyce, B. F., & Xing, L. (2007) · Current Osteoporosis Reports · doi:10.1007/s11914-007-0024-y · Cited by 339
Osteoclast-secreted CTHRC1 in the coupling of bone resorption to formation
Takeshita, S., Fumoto, T., Matsuoka, K., Park, K.-A., Aburatani, H., Kato, S., Ito, M., & Ikeda, K. (2013) · Journal of Clinical Investigation · doi:10.1172/jci69493 · Cited by 257
Tyrosine Phosphorylation of p85 Relieves Its Inhibitory Activity on Phosphatidylinositol 3-Kinase
Cuevas, B. D., Lu, Y., Mao, M., Zhang, J., LaPushin, R., Siminovitch, K. A., & Mills, G. B. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m100556200 · Cited by 256
Maruyama, Z., Yoshida, C. A., Furuichi, T., Amizuka, N., Ito, M., Fukuyama, R., Miyazaki, T., Kitaura, H., Nakamura, K., Fujita, T., et al. (2007) · Developmental Dynamics · doi:10.1002/dvdy.21187 · Cited by 232
RANKL/OPG; Critical role in bone physiology
Martin, T. J., & Sims, N. A. (2015) · Reviews in Endocrine and Metabolic Disorders · doi:10.1007/s11154-014-9308-6 · Cited by 213
Characterization of Regulatory Extracellular Vesicles from Osteoclasts
Huynh, N., VonMoss, L., Smith, D., Rahman, I., Felemban, M. F., Zuo, J., Rody, W. J., McHugh, K. P., & Holliday, L. S. (2016) · Journal of Dental Research · doi:10.1177/0022034516633189 · Cited by 196
Evaluation of Pharmaceuticals With a Novel 50-Hour Animal Model of Bone Loss
Tomimori, Y., Mori, K., Koide, M., Nakamichi, Y., Ninomiya, T., Udagawa, N., & Yasuda, H. (2009) · Journal of Bone and Mineral Research · doi:10.1359/jbmr.090217 · Cited by 184
Self-citationSingha, U. K., Jiang, Y., Yu, S., Luo, M., Lu, Y., Zhang, J., & Xiao, G. (2007) · Journal of Cellular Biochemistry · doi:10.1002/jcb.21411 · Cited by 181
Differentiation of mesenchymal stem cells into osteoblasts on honeycomb collagen scaffolds
George, J., Kuboki, Y., & Miyata, T. (2006) · Biotechnology and Bioengineering · doi:10.1002/bit.20939 · Cited by 148
Understanding Coupling between Bone Resorption and Formation
Andersen, T. L., Abdelgawad, M. E., Kristensen, H. B., Hauge, E. M., Rolighed, L., Bollerslev, J., Kjærsgaard-Andersen, P., & Delaisse, J.-M. (2013) · The American Journal of Pathology · doi:10.1016/j.ajpath.2013.03.006 · Cited by 137
Sato, N., Takahashi, N., Suda, K., Nakamura, M., Yamaki, M., Ninomiya, T., Kobayashi, Y., Takada, H., Shibata, K., Yamamoto, M., et al. (2004) · The Journal of Experimental Medicine · doi:10.1084/jem.20040689 · Cited by 132
Self-citationSuppression of NF-κB Increases Bone Formation and Ameliorates Osteopenia in Ovariectomized Mice
Alles, N., Soysa, N. S., Hayashi, J., Khan, M., Shimoda, A., Shimokawa, H., Ritzeler, O., Akiyoshi, K., Aoki, K., & Ohya, K. (2010) · Endocrinology · doi:10.1210/en.2010-0399 · Cited by 87
Self-citationStrength of TRAF6 signalling determines osteoclastogenesis
Kadono, Y., Okada, F., Perchonock, C. E., Jang, H. D., Lee, S. Y., Kim, N., & Choi, Y. (2005) · EMBO Reports · doi:10.1038/sj.embor.7400345 · Cited by 87
TNFα reverse signaling promotes sympathetic axon growth and target innervation
Kisiswa, L., Osório, C., Erice, C., Vizard, T. N., Wyatt, S. L., & Davies, A. M. (2013) · Nature Neuroscience · doi:10.1038/nn.3430 · Cited by 59
Bone marrow cell development and trabecular bone dynamics after ovariectomy in ddy mice
Sakai, A., Nishida, S., Okimoto, N., Okazaki, Y., Hirano, T., Norimura, T., Suda, T., & Nakamura, T. (1998) · Bone · doi:10.1016/s8756-3282(98)00121-5 · Cited by 53
Fei, Q., Guo, C.-J., Xu, X., Jianjun, G., Zhang, J., Chen, T., & Cui, D. (2010) · Acta Biochimica et Biophysica Sinica · doi:10.1093/abbs/gmq086 · Cited by 40
Vps33a Mediates RANKL Storage in Secretory Lysosomes in Osteoblastic Cells
Kariya, Y., Honma, M., Aoki, S., Chiba, A., & Suzuki, H. (2009) · Journal of Bone and Mineral Research · doi:10.1359/jbmr.090409 · Cited by 36
Self-citationSugamori, Y., Mise‐Omata, S., Maeda, C., Aoki, S., Tabata, Y., Murali, R., Yasuda, H., Udagawa, N., Suzuki, H., Honma, M., et al. (2016) · BioEssays · doi:10.1002/bies.201600104 · Cited by 32
Self-citationWatzl, C. (2006) · Current Protocols in Protein Science · doi:10.1002/0471140864.ps1911s43 · Cited by 8
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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
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Ono, T., Hayashi, M., Sasaki, F., & Nakashima, T. (2020) · Inflammation and Regeneration · doi:10.1186/s41232-019-0111-3 · Cited by 597
Self-citationZhu, G., Zhang, T., Chen, M., Yao, K., Huang, X., Zhang, B., Li, Y., Liu, J., Wang, Y., & Zhao, Z. (2021) · Bioactive Materials · doi:10.1016/j.bioactmat.2021.03.043 · Cited by 516
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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