Signaling pathways involved in osteoclast formation and activity. When RANKL binds RANK, multiple signaling pathways can be activated, including NF-κB, AKT, JNK, p38 MAPK, and ERK, resulting in subsequent activation of genes that regulate osteoclast formation, bone resorption, and survival. TRAF6 appears to play a central role in the activation of most of these pathways. AP1, activator protein 1; aPKC, atypical PKC; IκB, inhibitor of κB; ASK1, apoptosis signal–regulating kinase 1; BAD, Bcl-2–associated death promoter; IL-1R, IL-1 receptor; IKKα, IκB kinase α; IRAK, IL-1 receptor–associated kinase; JNKK, JNK kinase; MEK, MAPK/ERK kinase; MITF, microphthalmia transcription factor; MKK, MAPK kinase; NFATc1, nuclear factor of activated T cells cytoplasmic 1; PDK1, phosphoinositide-dependent protein kinase 1; RIP, receptor interacting protein; TNFR1, TNF receptor 1; TRADD, TNF receptor 1–associated death domain.