Figure 1.

Extracellular vesicles containing RANKL or RANK add increased complexity to the RANKL/RANK/osteoprotegerin signaling network that is at the core of bone biology. Until recently, RANKL stimulation of RANK to stimulate osteoclast formation and bone resorption by osteoclasts, and the ability of osteoprotegerin to bind RANKL and competitively inhibit this signaling, were considered the primary features of this network. Now data suggest that RANKL EVs can stimulate osteoclast formation and bone resorption through RANK stimulation, and RANK-EVs bind to RANKL on osteoblasts to stimulate RANKL reverse signaling and bone formation. The latter serves to couple bone resorption and bone formation. It is also possible that RANK-EVs can bind RANKL or RANKL-EVs and competitively inhibit their stimulation of RANK on osteoclasts. RANKL-EVs could serve as competitive inhibitors of RANK-EV’s stimulation of RANKL reverse signaling.