Coupling of bone resorption and formation by RANKL reverse signalling

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 and Hiroshi Suzuki
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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

Nature, 2018, vol. 561, issue 7722, 195-200

Abstract: 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.

Keywords: RANK Ligand (RANKL); Primary Mouse Osteoblasts; Gelatin Hydrogel Sheet; Osteoblast Mineralization; Serial Centrifugation (search for similar items in EconPapers)
Date: 2018
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Citations: View citations in EconPapers (3)

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DOI: 10.1038/s41586-018-0482-7

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