Fig. 1. Osteoclast differentiation and signaling pathways.

a Commitment to osteoclast differentiation is initiated by the engagement of RANKL with RANK. RANK activation recruits adaptor proteins, including TRAF6, thereby initiating the downstream signaling cascade and inducing the expression of osteoclast master regulators. The expression of RANK can be enhanced by additional factors to promote RANKL-induced osteoclast formation. b In committed osteoclasts, RANKL-RANK signaling cooperates with costimulatory molecules and promotes PLCγ-mediated Ca²⁺ signaling, which robustly amplifies NFATc1 levels. RANKL-RANK signaling also downregulates the negative regulators of NFATc1. c During maturation, committed osteoclasts undergo pronounced morphological changes. Cell adhesion molecules, including integrins and cadherins, regulate the activation of Rho family small GTPases and cytoskeletal organization, contributing to the formation of an actin ring/sealing zone. Additionally, RANKL-RANK signaling induces the expression of osteoclast fusion molecules through the activation of NFATc1, thereby contributing to multinucleation. d During resorption, osteoclasts digest inorganic and organic bone matrix by transporting protons and hydrolases through the ruffled border, as well as via endosomal/lysosomal vesicle trafficking. Transcytosis removes the resorbed bone material from the resorption pit. NC nucleus.