title: Autophagy proteins regulate the secretory component of osteoclastic bone resorption.
abstract: Osteoclasts resorb bone via the ruffled border, whose complex folds are generated by secretory lysosome fusion with bone-apposed plasma membrane. Lysosomal fusion with the plasmalemma results in acidification of the resorptive microenvironment and release of CatK to digest the organic matrix of bone. The means by which secretory lysosomes are directed to fuse with the ruffled border are enigmatic. We show that proteins essential for autophagy, including Atg5, Atg7, Atg4B, and LC3, are important for generating the osteoclast ruffled border, the secretory function of osteoclasts, and bone resorption in vitro and in vivo. Further, Rab7, which is required for osteoclast function, localizes to the ruffled border in an Atg5-dependent manner. Thus, autophagy proteins participate in polarized secretion of lysosomal contents into the extracellular space by directing lysosomes to fuse with the plasma membrane. These findings are in keeping with a putative link between autophagy genes and human skeletal homeostasis.
authors: Department of Pathology, Washington University Medical School, 660 S. Euclid Avenue, St. Louis, MO 63110, USA.
authors: Carl J
authors: CJ
authors: DeSelm
authors: Brian C
authors: BC
authors: Miller
authors: Wei
authors: W
authors: Zou
authors: Wandy L
authors: WL
authors: Beatty
authors: Eline
authors: E
authors: van Meel
authors: Yoshifumi
authors: Y
authors: Takahata
authors: Judith
authors: J
authors: Klumperman
authors: Sharon A
authors: SA
authors: Tooze
authors: Steven L
authors: SL
authors: Teitelbaum
authors: Herbert W
authors: HW
authors: Virgin
mesh_terms: D000818:Animals; D001343:Autophagy / Q000235:genetics; D000071187:Autophagy-Related Protein 5; D000071193:Autophagy-Related Protein 7; D000071183:Autophagy-Related Proteins; D001862:Bone Resorption / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D003546:Cysteine Endopeptidases / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000172:deficiency / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology* / Q000378:metabolism*
chemical_list: C495773:Atg5 protein, mouse; C502661:Atg7 protein, mouse; D000071187:Autophagy-Related Protein 5; D000071183:Autophagy-Related Proteins; C480860:Map1lc3b protein, mouse; D008869:Microtubule-Associated Proteins; C582881:Atg4b protein, mouse; D003546:Cysteine Endopeptidases; D000071193:Autophagy-Related Protein 7