TY - JOUR
T1 - Autophagy proteins regulate the secretory component of osteoclastic bone resorption
AU - DeSelm, Carl J.
AU - Miller, Brian C.
AU - Zou, Wei
AU - Beatty, Wandy L.
AU - van Meel, Helena
AU - Takahata, Yoshifumi
AU - Klumperman, Judith
AU - Tooze, Sharon A.
AU - Teitelbaum, Steven L.
AU - Virgin, Herbert W.
N1 - Funding Information:
H.W.V. was supported by U54 AI057160 Project 5 and RO1 AI0848887, S.L.T. was supported by AR057235, AR032788, AR057037, AR046523, and AR054618, and C.J.D. was supported by AG032795, from the National Institutes of Health. The contents of this study are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. H.v.M. and J.K. were supported by VICI grant 918.56.611 of the Netherlands Organization for Scientific Research (NWO). We thank Karen Green for assistance with electron microscopy and René Scriwanek, Viola Oorschot, and Marc van Peski for preparation of the CatK immunoelectron micrographs. The original hypothesis was formulated by C.J.D., B.C.M., H.W.V., and S.L.T. C.J.D. and B.C.M. performed almost all experiments. W.Z. provided experimental assistance. Y.T. performed in vitro bone nodule assays. W.L.B. performed electron microscopy and GFP-LC3 immunoelectron microscopy experiments. H.v.M. and J.K. performed CatK immunoelectron microscopy experiments. The manuscript was written by C.J.D., B.C.M., H.W.V., and S.L.T.; all authors commented on the manuscript, data, and conclusions before submission.
PY - 2011/11/15
Y1 - 2011/11/15
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=80755175726&partnerID=8YFLogxK
U2 - 10.1016/j.devcel.2011.08.016
DO - 10.1016/j.devcel.2011.08.016
M3 - Article
C2 - 22055344
AN - SCOPUS:80755175726
SN - 1534-5807
VL - 21
SP - 966
EP - 974
JO - Developmental cell
JF - Developmental cell
IS - 5
ER -