1.N.1 The Osteoclast Fusion Complex (OFC) Family
Osteoclast cell fusion to form syncytia is promoted by several proteins. Most importantly are DC-STAMP and OC-STAMP, but other proteins such as the V-type proton ATPase subunit d2, ATP6v0d2 (TC# 3.A.2.2.6), CD47, a leucocyte surface antigen of 323 aas (Q08722) and syncytin-1 (TC# 1.G.9.1.1) may play roles (Møller et al. 2016). The process is regulated by NFATc1, a master regulator of nuclear factor kappaB ligand-induced osteoclast differentiation. Kim et al. 2008 demonstrated a role for NFATc1 as a positive regulator of nuclear factor kappaB ligand-mediated osteoclast fusion as well as other fusion-inducing factors such as TNF-alpha. Exogenous overexpression of a constitutively active form of NFATc1 in bone marrow-derived monocyte/macrophage cells (BMMs) induces formation of multinucleated osteoclasts as well as the expression of fusion-mediating molecules such as the d2 isoform of vacuolar ATPase V(o) domain (Atp6v0d2) and the dendritic cell-specific transmembrane protein (DC-STAMP). Inactivation of NFATc1 by cyclosporin A treatment attenuates expression of Atp6v0d2 and DC-STAMP and the subsequent fusion of osteoclasts. Kim et al. 2008 showed that NFATc1 binds to the promoter regions of Atp6v0d2 and DC-STAMP in osteoclasts and directly induces their expression. Furthermore, overexpression of Atp6v0d2 and DC-STAMP rescues cell-cell fusion of preosteoclasts despite reduced NFATc1 activity. Thus, the NFATc1/Atp6v0d2 and DC-STAMP signaling axis plays a key role in the osteoclast multinucleation process, which is essential for efficient bone resorption.