Autophagy promotes osteoclast podosome disassembly and cell motility athrough the interaction of kindlin3 with LC3

Abstract

Osteoclasts are responsible for bone resorption and play an important role in physiological and pathological bone metabolism. Osteoclast migration across bone surfaces is essential for bone resorption, and a previous study demonstrated the role of autophagy in osteoclastogenesis and acid secretion. However, the role of autophagy in osteoclast migration remains unclear. Osteoclast migration requires the successive and rapid assembly and disassembly of podosome rings. In this study, we show that kindlin3, an important adaptor protein in the podosome, can interact with LC3B and undergo autophagy-mediated protein degradation to promote the disassembly of the podosome.Moreover, further analyses showed that the inhibition of autophagy increased kindlin3 levels and enhanced the interaction between kindlin3 and integrin β3. The over activation of integrins inhibits the disassembly of obsolete podosome rings, resulting in disorganization of the actin cytoskeleton and impaired migration in osteoclasts. Our results show that LC3B affects osteoclast migration and FAK/AKT activation by modulating integrin activation via a kindlin3-mediated inside-out signal from the extracellular matrix. Based on these results, we propose that LC3 is an important target for regulating osteoclast migration.