Signal transduction of TNF-α, RANKL and IL-1 in osteoclast differentiation and activation. TNF-α binds TNF receptor type 1 (TNFR1) and TNF receptor type 2 (TNFR2), RANKL binds RANK, and IL-1 binds IL-1 receptor (IL-1R). Both TNFR1 and TNFR2 bind TNF receptor-associated factor 2 (TRAF2), whereas IL-1R binds TNF receptor-associated factor 6 (TRAF6). RANK binds not only TRAF6, but also TRAF2 and other TNF receptor-associated factors (TRAFs). M-CSF, macrophage colony-stimulating factor.