Mechanical control of osteoclast fusion by membrane-cortex attachment and BAR proteins

Osteoclasts are multinucleated giant cells that are formed by the fusion of precursor cells. Cell-cell fusion is mediated by membrane protrusion driven by actin reorganization, but the role of membrane mechanics in this process is unknown. Utilizing live-cell imaging, optical tweezers, manipulation of membrane-to-cortex attachment (MCA), and genetic interference, we show that a decrease in plasma membrane (PM) tension is a mechanical prerequisite for osteoclast fusion. Upon RANKL-induced differentiation, ezrin expression in fusion progenitor cells is reduced, resulting in a decrease in MCA-dependent PM tension. A forced elevation of PM tension by reinforcing the MCA conversely suppresses cell-cell fusion. Mechanistically, reduced PM tension leads to membrane protrusive invadosome formation driven by membrane curvature-inducing/sensing BAR proteins, thereby promoting cell-cell fusion. These findings provide insights into the mechanism of cell-cell fusion under the control of membrane mechanics.