Secretory lysosomes containing degradative enzymes such as cathepsin K fuse with the ruffled border of osteoclast plasma membranes to promote the digestion and resorption of bone material. Although genome-wide association studies have hinted at a link between autophagy and bone homeostasis, the molecular details have remained elusive. Teitelbaum, Virgin and colleagues now reveal that the autophagy machinery is involved in generation of the osteoclast ruffled border and bone degradation (Dev. Cell 21, 966–974; 2011).

Autophagy is regulated by a cascade of events, including Atg7 (autophagy-related protein 7)-dependent conjugation of Atg5 to Atg12, and subsequent lipidation of LC3I (light chain 3 I) to form LC3II. The authors visualized LC3II at the ruffled border of wild-type mouse osteoclasts, but found that loss of Atg5 blocked this localization. Moreover, deletion of Atg5 or Atg7 inhibited accumulation of cathepsin-K-containing lysosomes at the ruffled border, and impaired bone degradation in vitro and in vivo. Rab7, which is known to mediate ruffled border formation, was also mislocalized in Atg5-null osteoclasts.

These results suggest that Atg5 functions upstream of Rab7 to modulate ruffled border formation. Indeed, this membrane structure was absent or aberrantly formed in Atg5-deficient osteoclasts. The authors propose that autophagy proteins mediate fusion of secretory lysosomes with the plasma membrane to form the ruffled border and regulate bone resorption, revealing a previously unappreciated role for autophagy machinery in osteoclast polarized secretion.