Coupling of bone resorption and formation by RANKL reverse signalling View Full Text


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

2018-09-05

AUTHORS

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, Hiroshi Suzuki

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. More... »

PAGES

195-200

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/s41586-018-0482-7

DOI

http://dx.doi.org/10.1038/s41586-018-0482-7

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1106659952

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/30185903


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32 schema:description 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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39 RANKL function
40 Recent studies
41 Runt
42 acceptor
43 activation
44 activator
45 bone formation
46 bone remodelling
47 bone resorption
48 coupling
49 cytoplasmic tail
50 factor 2
51 formation
52 function
53 important role
54 inhibition
55 inhibition of osteoclastogenesis
56 mice
57 motif
58 mutant mice
59 mutations
60 osteoblastic RANKL
61 osteoclast precursors
62 osteoclastogenesis
63 osteoclasts
64 osteocytic RANKL
65 pathway
66 pharmacological targets
67 point mutations
68 potential pharmacological target
69 precursors
70 proline-rich motif
71 rank
72 receptor activator
73 remodelling
74 resorption
75 reverse signaling
76 role
77 signaling
78 study
79 surface
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81 target
82 transcription factor 2
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