RRC ID 35754
Author Takegahara N, Kim H, Mizuno H, Sakaue-Sawano A, Miyawaki A, Tomura M, Kanagawa O, Ishii M, Choi Y.
Title Involvement of Receptor Activator of Nuclear Factor-κB Ligand (RANKL)-induced Incomplete Cytokinesis in the Polyploidization of Osteoclasts.
Journal J Biol Chem
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.
Volume 291(7)
Pages 3439-54
Published 2016-2-12
DOI 10.1074/jbc.M115.677427
PII S0021-9258(20)45165-8
PMID 26670608
PMC PMC4751386
MeSH Animals Benzimidazoles / pharmacology Biomarkers / metabolism Bone Marrow Cells / cytology Bone Marrow Cells / metabolism Bone Marrow Cells / pathology Cell Fusion Cell Nucleus / drug effects Cell Nucleus / metabolism* Cell Nucleus / pathology Cells, Cultured Crosses, Genetic Cytokinesis* / drug effects Luminescent Proteins / genetics Luminescent Proteins / metabolism Male Mice, Transgenic Myeloid Progenitor Cells / cytology Myeloid Progenitor Cells / drug effects Myeloid Progenitor Cells / metabolism* Myeloid Progenitor Cells / pathology Osteoclasts / cytology Osteoclasts / drug effects Osteoclasts / metabolism* Osteoclasts / pathology Osteogenesis / drug effects Osteolysis / metabolism* Osteolysis / pathology Phosphorylation / drug effects Polyploidy* Protein Processing, Post-Translational / drug effects Proto-Oncogene Proteins c-akt / agonists Proto-Oncogene Proteins c-akt / antagonists & inhibitors Proto-Oncogene Proteins c-akt / metabolism Quinoxalines / pharmacology RANK Ligand / metabolism* Recombinant Fusion Proteins / genetics Recombinant Fusion Proteins / metabolism
IF 4.238
Times Cited 11
Mice RBRC02704 RBRC02709