PHOSPHATIDYLSERINE EXPOSURE AND EXTRACELLULAR ANNEXIN A5 WEAKEN THE ACTIN CORTEX IN OSTEOCLAST FUSION.

Diverse cell-cell fusions involve intracellular Ca signaling, non-apoptotic exposure of phosphatidylserine (PS) at the surface of fusion-committed cells and binding of extracellular Annexin A5 (Anx A5). Here we focus on the cell fusion stage of formation of bone-resorbing multinucleated osteoclasts and report that each of the listed hallmarks of cell fusion represents a step in a novel bidirectional signaling pathway. A rise in intracellular Ca2+ activates a lipid scramblase that translocates PS from the inner to the outer leaflet of the plasma membrane. This redistribution is enhanced by extracellular Anx A5 binding to cell surface PS. Depletion of PS in the inner leaflet weakens actin cortex-plasma membrane attachment mediated by ezrin/radixin/moesin (ERM) proteins, as evidenced by the preferential localization of cortex detachment areas within PS-enriched regions at the surface of the cells. Weakening of the cortex-membrane connection by Anx A5 or by adding an inhibitor of the ERM proteins promotes osteoclast fusion. We propose that this pathway facilitates osteoclast fusion and other cell-cell fusions by promoting membrane deformations required for formation of prefusion membrane contacts. Additionally, the elevated tension in the cortex detachment region of the membrane, suggested by our theoretical analysis, promotes fusion pore expansion.