title: Interleukin-1β promotes the LC3-mediated secretory function of osteoclast precursors by stimulating the Ca²⁺-dependent activation of ERK.
abstract: Bone resorption by osteoclasts requires the release of secretory lysosomes containing cathepsin K, which degrades the organic bone matrix. The activity of this secretory function is determined by the level of lipidation of microtubule-associated protein 1 light chain 3 (LC3). Although the inflammatory cytokine IL-1β increases osteoclast activity, the underlying mechanism(s) remains undefined. In our present study, we found that IL-1β accelerates the release of cathepsin K from osteoclast precursors by increasing the cleavage and lipidation of LC3 and the subsequent formation of lipid-bound LC3-II containing secretory lysosomes. IL-1β increased LC3-II formation within osteoclast precursors through a process that is dependent on increases in the intracellular Ca(2+) levels. In addition, IL-1β was found to act synergistically with RANKL to increase ERK activation in a Ca(2+)-dependent manner. More importantly, Atg7-deficient osteoclast precursors, which showed impaired lipidation of LC3-I, did not exhibit IL-1β-mediated increases in cathepsin K secretion. Thus, IL-1β promotes LC3-II formation through the Ca(2+)-dependent activation of ERK, which triggers the release of cathepsin K. These findings provide evidence for a molecular mechanism through which IL-1β enhances the secretory function of osteoclast precursors.
authors.affiliation: Department of Biomedical Sciences, University of Ulsan College of Medicine, Asan Medical Center, Seoul 138-736, Republic of Korea; Cell Dysfunction Research Center and BMIT, University of Ulsan College of Medicine, Seoul 138-736, Republic of Korea.
authors.forename: Yeon-Ho
authors.initials: YH
authors.lastname: Chung
authors.affiliation: Department of Biomedical Sciences, University of Ulsan College of Medicine, Asan Medical Center, Seoul 138-736, Republic of Korea; Cell Dysfunction Research Center and BMIT, University of Ulsan College of Medicine, Seoul 138-736, Republic of Korea.
authors.forename: Bongkun
authors.initials: B
authors.lastname: Choi
authors.affiliation: Department of Biomedical Sciences, University of Ulsan College of Medicine, Asan Medical Center, Seoul 138-736, Republic of Korea; Cell Dysfunction Research Center and BMIT, University of Ulsan College of Medicine, Seoul 138-736, Republic of Korea.
authors.forename: Da-Hyun
authors.initials: DH
authors.lastname: Song
authors.affiliation: Department of Biomedical Sciences, University of Ulsan College of Medicine, Asan Medical Center, Seoul 138-736, Republic of Korea; Department of Anatomy and Cell Biology, University of Ulsan College of Medicine, Asan Medical Center, Seoul 138-736, Republic of Korea; Cell Dysfunction Research Center and BMIT, University of Ulsan College of Medicine, Seoul 138-736, Republic of Korea.
authors.forename: Youngsup
authors.initials: Y
authors.lastname: Song
authors.affiliation: Department of Biomedical Sciences, University of Ulsan College of Medicine, Asan Medical Center, Seoul 138-736, Republic of Korea; Department of Anatomy and Cell Biology, University of Ulsan College of Medicine, Asan Medical Center, Seoul 138-736, Republic of Korea; Cell Dysfunction Research Center and BMIT, University of Ulsan College of Medicine, Seoul 138-736, Republic of Korea.
authors.forename: Sang-Wook
authors.initials: SW
authors.lastname: Kang
authors.affiliation: Department of Anatomy and Cell Biology, University of Ulsan College of Medicine, Asan Medical Center, Seoul 138-736, Republic of Korea; Cell Dysfunction Research Center and BMIT, University of Ulsan College of Medicine, Seoul 138-736, Republic of Korea.
authors.forename: Seung-Yong
authors.initials: SY
authors.lastname: Yoon
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine, Asan Medical Center, Seoul 138-736, Republic of Korea; Cell Dysfunction Research Center and BMIT, University of Ulsan College of Medicine, Seoul 138-736, Republic of Korea.
authors.forename: Seong Who
authors.initials: SW
authors.lastname: Kim
authors.affiliation: Department of Ophthalmology, Yonsei University College of Medicine, Seoul 135-720, Republic of Korea.
authors.forename: Hyung Keun
authors.initials: HK
authors.lastname: Lee
authors.affiliation: Department of Biomedical Sciences, University of Ulsan College of Medicine, Asan Medical Center, Seoul 138-736, Republic of Korea; Department of Anatomy and Cell Biology, University of Ulsan College of Medicine, Asan Medical Center, Seoul 138-736, Republic of Korea; Cell Dysfunction Research Center and BMIT, University of Ulsan College of Medicine, Seoul 138-736, Republic of Korea. Electronic address: ejchang@amc.seoul.kr.
authors.forename: Eun-Ju
authors.initials: EJ
authors.lastname: Chang
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001853:Bone Marrow / Q000187:drug effects / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D056657:Cathepsin K / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D053583:Interleukin-1beta / Q000494:pharmacology*; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D053583:Interleukin-1beta; C480860:Map1lc3b protein, mouse; D008869:Microtubule-Associated Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D056657:Cathepsin K; D002118:Calcium
keywords: Cathepsin K; IL-1β; Intracellular Ca(2+); LC3; Osteoclast