Table 1.

Biological targets involved in monocyte-macrophages fusion and multinucleation (M-FM).

Biological Target	Role in M-FM	Refs
CD44/Matrix metallopeptidase 9 (CD44/MMP-9)	▪Enhances the motility signals for stimulating cells to migrate and fuse.	[45]
Monocyte chemoattractant protein-1/C-C chemokine receptor type 2 (MCP-1/CCR2)	▪Crucial for the formation of mature multinucleated OCs.	[49,50]
CD9	▪Permissive fusogen.	[51]
Dendritic cell-specific transmembrane protein (DC-STAMP)	▪OCs-specific fusogen.	[37,53]
OC-stimulatory transmembrane protein (OC-STAMP)	▪OCs-specific fusogen.	[44]
Syncitin-1	▪Drives the fusion of the plasma membranes lipid bilayers. ▪Drives the fusion between multinucleated cells rather than mononuclear pre-OCs.	[58]
Sialic acid-binding immunoglobulin-type lectin 15 (Siglec-15)	▪Key to the formation of the actin ring. ▪Key to the formation of multinucleated OCs.	[59,60,61,62,63]
Ras-related protein Rab-27a (Rab27a)	▪Mediates lysosomes trafficking and membrane fusion. ▪Regulates the transport of LRO to modulate multinucleation and cell size in OCs.	[64]
Osteoclastogenesis-associated transmembrane protein-1 (Ostm1)	▪Inhibits M-FM by targeting NFATc1.	[65]
miR7b	▪Targets and inhibits DC-STAMP.	[37]
miR30a	▪Targets and inhibits DC-STAMP.	[35]
miR-26a	▪Targets CTGF/CCN2 and inhibits DC-STAMP.	[66]
CD47	▪Key to the fusion of two mono-nucleated partners or mono- and multinucleated partners. ▪Promotes the formation of large OCs and reduces the formation of smaller OCs.	[58]
Macrophage fusion receptor (MFR)	▪Plays a role in macrophage-macrophage adhesion/fusion leading to multinucleation.	[7,10]
E-cadherin	▪Drives the formation of dynamic membrane protrusions necessary for migration and fusion. ▪Promotes the formation of multinucleated OCs.	[7]
CD-26	▪Key to the formation of multinucleated OCs.	[68]
CD-47	▪Key to the fusion of two mono-nucleated partners or mono- and multinucleated partners. ▪Favour the formation of large OCs and to reduce the formation of smaller OCs.	[69]
Src non-receptor tyrosine kinase (c-Src)	▪Maintains the dynamic organization of the ZLS. ▪Key to the formation of multinucleated OCs.	[22,73]
Human protein ‘SH3 and PX domains 2A’ (Tsk5)	▪Promotes the formation of podosomes and fusion-competent protrusions.	[24]
C-C chemokine receptor type 1 (CCR-1)	▪Key to the cell fusion.	[22]
Rapamycin-insensitive companion of TOR (RICTOR)	▪Regulates OCs fusion by up-regulating DC-STAMP.	[23]
Tenascin x (TNX)	▪Suppresses OCs multinucleation.	[78]
Dynamin	▪Key to the formation of multinucleated OCs.	[79]
Two-pore channel 2 (TPC2)	▪Downstream effector of RANKL involved in differentiation, multinucleation.	[80]
Fibronectin leucine-rich transmembrane protein 2 (Flrt2)	▪Key to the formation of multinucleated OCs.	[81]
Calcium release-activated channels (CRAC-C channels)	▪Key to the formation of multinucleated OCs.	[82]
Transcription factor Spi-C (SPIC)	▪Governs both early and late stages of OCs differentiation among which multinucleation and bone-resorbing functions.	[83]
Crk-associated substrate (Cas)	▪Key to actin cytoskeletal reorganization, actin ring formation and multinucleation of OCs	[85]
Luman	▪Regulates the expression, localization and stability of DC-STAMP.	[70]
Vacuolar ATPase (ATP6v0d2)	▪Key to the formation of multinucleated OCs.	[71]
DAP-12	▪Key for acquiring fusion competence. ▪Key to the formation of multinucleated OCs.	[72]
OSCAR-FcRy	▪Key for acquiring fusion competence.	[73]
Transglutaminases	▪Regulates migration and fusion of pre-OC.	[74]
P2 × 7	▪Key to the formation of multinucleated OCs in vitro.	[75]
P2 × 5	▪Key to the formation of multinucleated OCs in vitro.	[76,77]
miR124	▪Targets and inhibits Rab27a.	[67]