RANKL/RANK signaling in osteoclast formation and DC activation. (A). RANKL/RANK interactions enhances osteoclast differentiation and bone resorption. (B) RANKL/RANK interactions also occur in the immune system, driving dendritic cell survival, and activation. (C) Signaling occurs via the recruitment of adaptor molecules, most importantly TNF receptor-associated factor 6 (TRAF6), which activates downstream signaling pathways, including that of nuclear factor-κB (NFκB) as well as mitogen-associated protein kinases (MAPK) such as p38, c-Jun N-terminal protein kinases (JNK), and the extracellular signal-regulated kinases (ERK). TRAF6 also complexes with c-Src to activate the antiapoptotic serine/threonine kinase AKT/PKB. (D) Immature interstitial DCs co-express both RANKL and RANK, and demonstrate autocrine stimulation. However, as these cells mature, they down-regulate RANKL and become dependent on exogenous factors.