Figure 1.

RANK–RANKL interactions under the canopy of bone remodeling compartments: old and new paradigms. The canopy is generated by bone lining cells and insulates a basic multicellular unit with osteoclasts (OC) and osteoblasts (OB). OC and OB precursors are recruited under the canopy, from respectively bone marrow- and blood stream-supplied hematopoietic stem cells and bone marrow-issued mesenchymal stromal cells. In the old and well-demonstrated paradigm, RANKL secreted by OB induces OC differentiation through RANK intracellular signaling (RANKL-RANK), while a new paradigm proposes a reverse signaling through RANKL intracellular signaling (RANK-RANKL) mediated by RANK-bearing extracellular vesicles EVs from OC [32]. RANK: receptor activator of nuclear factor kappa-B; RANKL: RANK ligand.