Coupling of bone resorption and formation by RANKL reverse signalling
- PMID: 30185903
- DOI: 10.1038/s41586-018-0482-7
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.
Comment in
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Receptor becomes a ligand to control bone remodelling.Nature. 2018 Sep;561(7722):180-181. doi: 10.1038/d41586-018-05960-x. Nature. 2018. PMID: 30194368 No abstract available.
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RANKL reverse signalling and bone.Nat Rev Endocrinol. 2018 Nov;14(11):627. doi: 10.1038/s41574-018-0094-1. Nat Rev Endocrinol. 2018. PMID: 30206382 No abstract available.
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RANKL reverse signalling and bone.Nat Rev Rheumatol. 2018 Nov;14(11):623. doi: 10.1038/s41584-018-0093-6. Nat Rev Rheumatol. 2018. PMID: 30262868 No abstract available.
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References
-
- Sims, N. A. & Martin, T. J. Coupling the activities of bone formation and resorption: a multitude of signals within the basic multicellular unit. Bonekey Rep. 3, 481 (2014).
-
- Florencio-Silva, R., Sasso, G. R., Sasso-Cerri, E., Simoes, M. J. & Cerri, P. S. Biology of bone tissue: structure, function, and factors that influence bone cells. BioMed Res. Int. 2015, 421746 (2015).
-
- Kong, Y. Y. et al. OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis. Nature 397, 315–323 (1999).
-
- Suda, T. et al. Modulation of osteoclast differentiation and function by the new members of the tumor necrosis factor receptor and ligand families. Endocr. Rev. 20, 345–357 (1999).
-
- Nakashima, T. et al. Evidence for osteocyte regulation of bone homeostasis through RANKL expression. Nat. Med. 17, 1231–1234 (2011).
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