Fig. 2
Molecular mechanisms underlying osteoclast differentiation. RANKL, the master regulator of osteoclastogenesis, is expressed by osteocytes and Bglaphi osteoblasts. Dcnhi osteoblasts locally produce OPG to inhibit osteoclast differentiation and activation. RANKL binding to RANK expressed by osteoclast progenitors results in the activation of signaling cascades including MAPK and NF-κB pathways via TRAF6 and TAK1. The RANKL/RANK signal cooperates with signaling from ITAM-containing immunoglobulin-like receptors such as TREM-2, SIRP ββ, Siglec-15, OSCAR, PIR-A, and FcγRIII. These signaling cascades ultimately lead to the auto-amplification of NFATc1, the master transcription factor of osteoclastogenesis