fig2

Figure 2. Regulation of RANK-containing EV production. We hypothesize that when RANK is internalized, an element of the normal receptor life cycle, it can either be recycled back to the plasma membrane, where it would be available for continued stimulation by RANKL. This would favor bone resorption. Alternatively, it could be sorted into a retrograde pathway that could lead to the Golgi for reuse of RANK, to the lysosome for degradation, or to multivesicular bodies, some of which would fuse with the plasma membrane and release RANK-EVs. All the retrograde pathways would remove RANK from the plasma membrane surface, and thus reduce stimulation by RANKL. In addition, shedding of RANK-EVs would also stimulate the RANKL reverse pathway and bone formation. If this idea is correct, shifts in the sorting of RANK could have profound effects on both bone resorption and bone formation, and understanding the underlying mechanisms may identify new strategies for treating bone disease.