Moesin controls cell-cell fusion and osteoclast function

Cell-cell fusion is an evolutionarily conserved process that is essential for many functions, including the formation of bone-resorbing multinucleated osteoclasts. Osteoclast multinucleation involves dynamic interactions between the actin cytoskeleton and the plasma membrane that are still poorly characterized. We found that moesin, a cytoskeletal linker protein member of the Ezrin, radixin, and moesin (ERM) protein family, plays a critical role in both osteoclast fusion and function. Moesin inhibition favors osteoclast multinucleation as well as HIV-1- and inflammation-induced cell fusion. Accordingly, moesin depletion decreases membrane-to-cortex attachment and enhances the formation of tunneling nanotubes, F-actin-based intercellular bridges triggering cell-cell fusion. In addition, moesin regulates the formation of the sealing zone, a key structure determining osteoclast bone resorption area, and thus controls bone degradation via a β3-integrin/RhoA/SLK pathway. Finally, moesin-deficient mice have reduced bone density and increased osteoclast abundance and activity. These findings provide a better understanding of cell-cell fusion and osteoclast biology, opening new opportunities to specifically target osteoclasts in bone disease therapy.