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Coupling of bone resorption and formation by RANKL reverse signalling

Author

Listed:
  • Yuki Ikebuchi

    (the University of Tokyo)

  • Shigeki Aoki

    (the University of Tokyo)

  • Masashi Honma

    (the University of Tokyo)

  • Madoka Hayashi

    (the University of Tokyo)

  • Yasutaka Sugamori

    (Tokyo Medical and Dental University)

  • Masud Khan

    (Tokyo Medical and Dental University)

  • Yoshiaki Kariya

    (the University of Tokyo)

  • Genki Kato

    (Tokyo Medical and Dental University)

  • Yasuhiko Tabata

    (Kyoto University)

  • Josef M. Penninger

    (Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna Biocenter)

  • Nobuyuki Udagawa

    (Matsumoto Dental University)

  • Kazuhiro Aoki

    (Tokyo Medical and Dental University)

  • Hiroshi Suzuki

    (the University of Tokyo)

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.

Suggested Citation

  • Yuki Ikebuchi & Shigeki Aoki & Masashi Honma & Madoka Hayashi & Yasutaka Sugamori & Masud Khan & Yoshiaki Kariya & Genki Kato & Yasuhiko Tabata & Josef M. Penninger & Nobuyuki Udagawa & Kazuhiro Aoki , 2018. "Coupling of bone resorption and formation by RANKL reverse signalling," Nature, Nature, vol. 561(7722), pages 195-200, September.
    • Handle: RePEc:nat:nature:v:561:y:2018:i:7722:d:10.1038_s41586-018-0482-7
    DOI: 10.1038/s41586-018-0482-7
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    Cited by:

    1. Dane Huang & Chao Zhao & Ruyue Li & Bingyi Chen & Yuting Zhang & Zhejun Sun & Junkang Wei & Huihao Zhou & Qiong Gu & Jun Xu, 2022. "Identification of a binding site on soluble RANKL that can be targeted to inhibit soluble RANK-RANKL interactions and treat osteoporosis," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    2. Maki Uenaka & Erika Yamashita & Junichi Kikuta & Akito Morimoto & Tomoka Ao & Hiroki Mizuno & Masayuki Furuya & Tetsuo Hasegawa & Hiroyuki Tsukazaki & Takao Sudo & Keizo Nishikawa & Daisuke Okuzaki & , 2022. "Osteoblast-derived vesicles induce a switch from bone-formation to bone-resorption in vivo," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    3. Jarred M. Whitlock & Evgenia Leikina & Kamran Melikov & Luis Fernandez Castro & Sandy Mattijssen & Richard J. Maraia & Michael T. Collins & Leonid V. Chernomordik, 2023. "Cell surface-bound La protein regulates the cell fusion stage of osteoclastogenesis," Nature Communications, Nature, vol. 14(1), pages 1-19, December.

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