Figure 1.

Signaling cascades during osteoclastogenesis. Receptor activator of nuclear factor-κB ligand (RANKL)-RANK binding results in the recruitment of tumor necrosis factor receptor-associated factor 6 (TRAF 6), which activates nuclear factor-κB (NF-κB) and mitogen-activated protein kinases. RANKL also stimulates the induction of c-Fos through NF-κB and Ca²⁺/calmodulin-dependent protein kinase IV (CaMKIV). NF-κB and c-Fos are important for the robust induction of nuclear factor of activated T cells cytoplasmic 1 (NFATc1). Several costimulatory receptors associate with the immunoreceptor tyrosine-based activation motif (ITAM)-harboring adaptors, Fc receptor common γ subunit (FcRγ), and DNAX-activating protein 12 (DAP12): osteoclast-associated receptor (OSCAR) and triggering receptor expressed in myeloid cells 2 (TREM2) associate with FcRγ, and signal-regulatory protein β1 (SIRPβ1) and paired immunoglobulin-like receptor-A (PIR-A) associate with DAP12. RANK signaling and ITAM signaling cooperate to phosphorylate phospholipase Cγ (PLCγ) and activate calcium signaling, the latter of which is critical for the activation and autoamplification of NFATc1. Tec family tyrosine kinases (Tec and Btk) activated by RANK are important for the formation of the osteoclastogenic signaling complex composed of Tec kinases, B-cell linker (BLNK)/SH2 domain-containing leukocyte protein of 76 kDa (SLP76) (activated by ITAM-spleen tyrosine kinase, or Syk), and PLCγ, all of which are essential for the efficient phosphorylation of PLCγ. AP-1, activator protein 1; CREB, cyclic adenosine monophosphate responsive-element-binding protein; MITF, microphthalmia-associated transcription factor; TRAP, tartrate-resistant acid phosphatase.