Tunneling Nanotube-Mediated Filamin A Transport Mechanosensitively Programs Osteoclastogenesis in Myeloma Bone Disease

Intercellular communications between multiple myeloma (MM) cells and osteoclast precursor cells (pre-OCs) contribute extensively to the occurrence and development of myeloma-related bone destruction. However, key interacting modes and the substances exchanged involved in this communication remain unclear. In this study, we discover that tunnelling nanotubes (TNT) directly connect MM and pre-OCs. Using stable isotope labeling with amino acids in cell culture (SILAC) assay and a positive-negative double selection strategy, we identify Filamin-A (FLNA) as a major protein transported from MM to pre-OCs. FLNA acts as a molecular clutch linking ECM-bound MAC1 to the cytoskeleton, activating Rho and MAPK signaling pathways and promoting F-actin polymerization, which subsequently enhances osteoclast differentiation by modulating cellular stiffness, traction force, and deformability. Additionally, FLNA directly binds vinculin and promotes its recruitment to podosome, thereby enhancing functions of podosome and bone resorption capacity of osteoclasts. Conditional depletion of Flna in mice suppresses podosome activity and reduces stiffness, traction force, and deformability in pre-OCs, leading to significantly impaired osteoclast differentiation and increased bone mass. In the Vk*MYC mouse model of myeloma, administration of the TNT inhibitor Latrunculin B disrupts FLNA transport to osteoclasts and alleviates osteolytic bone disease. These findings highlight the critical role of MM-transferred FLNA in osteoclastogenesis and suggest that targeting TNTs may represent a therapeutic strategy to limit pathological bone resorption associated with multiple myeloma.