Coupling of bone resorption and formation by RANKL reverse signalling

Nature. 2018 Sep;561(7722):195-200. doi: 10.1038/s41586-018-0482-7. Epub 2018 Sep 5.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Substitution
  • Animals
  • Bone Resorption / metabolism*
  • Cell Differentiation
  • Core Binding Factor Alpha 1 Subunit / metabolism
  • Cross-Linking Reagents / chemistry
  • Cytoplasmic Vesicles / metabolism
  • Female
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Osteoblasts / cytology
  • Osteoblasts / metabolism
  • Osteoclasts / cytology
  • Osteoclasts / metabolism
  • Osteogenesis*
  • RANK Ligand / chemistry
  • RANK Ligand / deficiency
  • RANK Ligand / genetics
  • RANK Ligand / metabolism*
  • Receptor Activator of Nuclear Factor-kappa B / genetics
  • Receptor Activator of Nuclear Factor-kappa B / metabolism
  • Signal Transduction*


  • Core Binding Factor Alpha 1 Subunit
  • Cross-Linking Reagents
  • RANK Ligand
  • Receptor Activator of Nuclear Factor-kappa B
  • Runx2 protein, mouse
  • Tnfrsf11a protein, mouse
  • Tnfsf11 protein, mouse