title: Involvement of Receptor Activator of Nuclear Factor-κB Ligand (RANKL)-induced Incomplete Cytokinesis in the Polyploidization of Osteoclasts.
abstract: Osteoclasts are specialized polyploid cells that resorb bone. Upon stimulation with receptor activator of nuclear factor-κB ligand (RANKL), myeloid precursors commit to becoming polyploid, largely via cell fusion. Polyploidization of osteoclasts is necessary for their bone-resorbing activity, but the mechanisms by which polyploidization is controlled remain to be determined. Here, we demonstrated that in addition to cell fusion, incomplete cytokinesis also plays a role in osteoclast polyploidization. In in vitro cultured osteoclasts derived from mice expressing the fluorescent ubiquitin-based cell cycle indicator (Fucci), RANKL induced polyploidy by incomplete cytokinesis as well as cell fusion. Polyploid cells generated by incomplete cytokinesis had the potential to subsequently undergo cell fusion. Nuclear polyploidy was also observed in osteoclasts in vivo, suggesting the involvement of incomplete cytokinesis in physiological polyploidization. Furthermore, RANKL-induced incomplete cytokinesis was reduced by inhibition of Akt, resulting in impaired multinucleated osteoclast formation. Taken together, these results reveal that RANKL-induced incomplete cytokinesis contributes to polyploidization of osteoclasts via Akt activation.
authors.affiliation: From the Next Generation Optical Immune-imaging, WPI-Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan, the Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104, takegaharanor@gmail.com.
authors.forename: Noriko
authors.initials: N
authors.lastname: Takegahara
authors.affiliation: the Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104.
authors.forename: Hyunsoo
authors.initials: H
authors.lastname: Kim
authors.affiliation: the Department of Immunology and Cell Biology, Graduate School of Medicine and Frontier Biosciences, WPI-Immunology Frontier Research Center, Osaka University, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan, the CREST, Japan Science and Technology Agency, 5 Sanban-cho, Chiyoda-ku, Tokyo 102-0075, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Mizuno
authors.affiliation: the Laboratory for Cell Function and Dynamics, Advanced Technology Development Group, Brain Science Institute, RIKEN, Wako-city, Saitama 351-0198, Japan.
authors.forename: Asako
authors.initials: A
authors.lastname: Sakaue-Sawano
authors.affiliation: the Laboratory for Cell Function and Dynamics, Advanced Technology Development Group, Brain Science Institute, RIKEN, Wako-city, Saitama 351-0198, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Miyawaki
authors.affiliation: the Laboratory for Autoimmune Regulation, Research Center for Allergy and Immunology, RIKEN, Yokohama City, Kanagawa 230-0045, Japan, the Laboratory of Immunology, Faculty of Pharmacy, Osaka-Ohtani University, 3-11-1 Nishikiorikita, Tondabayashi-city, Osaka 584-8540, Japan, and.
authors.forename: Michio
authors.initials: M
authors.lastname: Tomura
authors.affiliation: the Department of Molecular Preventive Medicine, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-033, Japan.
authors.forename: Osami
authors.initials: O
authors.lastname: Kanagawa
authors.affiliation: the Department of Immunology and Cell Biology, Graduate School of Medicine and Frontier Biosciences, WPI-Immunology Frontier Research Center, Osaka University, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan, the CREST, Japan Science and Technology Agency, 5 Sanban-cho, Chiyoda-ku, Tokyo 102-0075, Japan.
authors.forename: Masaru
authors.initials: M
authors.lastname: Ishii
authors.affiliation: the Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104, ychoi3@mail.med.upenn.edu.
authors.forename: Yongwon
authors.initials: Y
authors.lastname: Choi
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D015415:Biomarkers / Q000378:metabolism; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D002459:Cell Fusion; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D003433:Crosses, Genetic; D048749:Cytokinesis / Q000187:drug effects; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D008822:Mice, Transgenic; D023461:Myeloid Progenitor Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D010012:Osteogenesis / Q000187:drug effects; D010014:Osteolysis / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D011123:Polyploidy; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D011810:Quinoxalines / Q000494:pharmacology; D053245:RANK Ligand / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C532657:1,3-dihydro-1-(1-((4-(6-phenyl-1H-imidazo(4,5-g)quinoxalin-7-yl)phenyl)methyl)-4-piperidinyl)-2H-benzimidazol-2-one; D001562:Benzimidazoles; D015415:Biomarkers; D008164:Luminescent Proteins; D011810:Quinoxalines; D053245:RANK Ligand; D011993:Recombinant Fusion Proteins; C505689:Tnfsf11 protein, mouse; C514862:Akt1 protein, mouse; D051057:Proto-Oncogene Proteins c-akt
keywords: cell biology; cell division; cell proliferation; flow cytometry; imaging; incomplete cytokinesis; osteoclast; polyploidy