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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.

References associated with 1.N.1 family:

Chiu, Y.H., E. Schwarz, D. Li, Y. Xu, T.R. Sheu, J. Li, K.L. de Mesy Bentley, C. Feng, B. Wang, J.C. Wang, L. Albertorio-Saez, R. Wood, M. Kim, W. Wang, and C.T. Ritchlin. (2017). Dendritic Cell-Specific Transmembrane Protein (DC-STAMP) Regulates Osteoclast Differentiation via the Ca2+ /NFATc1 Axis. J Cell Physiol 232: 2538-2549. 27723141
Kalita, M.M. and W.B. Fischer. (2017). Decoupled side chain and backbone dynamics for proton translocation - M2 of influenza A. J Mol Model 23: 212. 28646429
Kim, K., S.H. Lee, J. Ha Kim, Y. Choi, and N. Kim. (2008). NFATc1 induces osteoclast fusion via up-regulation of Atp6v0d2 and the dendritic cell-specific transmembrane protein (DC-STAMP). Mol Endocrinol 22: 176-185. 17885208
Møller, A.M., J.M. Delaissé, and K. Søe. (2016). Osteoclast Fusion: Time-Lapse Reveals Involvement of CD47 and Syncytin-1 at Different Stages of Nuclearity. J Cell Physiol. [Epub: Ahead of Print] 27714815
Takagi, T., H. Inoue, N. Takahashi, R. Katsumata-Tsuboi, and M. Uehara. (2017). Sulforaphene attenuates multinucleation of pre-osteoclasts by suppressing expression of cell-cell fusion-associated genes DC-STAMP, OC-STAMP, and Atp6v0d2. Biosci. Biotechnol. Biochem. 81: 1220-1223. 28136694
Zhang, C., C.E. Dou, J. Xu, and S. Dong. (2014). DC-STAMP, the key fusion-mediating molecule in osteoclastogenesis. J Cell Physiol 229: 1330-1335. 24420845