Involvement of Receptor Activator of Nuclear Factor-κB Ligand (RANKL)-induced Incomplete Cytokinesis in the Polyploidization of Osteoclasts

• Published in: The Journal of biological chemistry 2016-02, Vol.291 (7), p.3439-3454
• Main Authors: Takegahara, Noriko, Kim, Hyunsoo, Mizuno, Hiroki, Sakaue-Sawano, Asako, Miyawaki, Atsushi, Tomura, Michio, Kanagawa, Osami, Ishii, Masaru, Choi, Yongwon
• Format: Article
• Language: English
• Subjects: Animals; Benzimidazoles - pharmacology; Biomarkers - metabolism; Bone Marrow Cells - cytology; Bone Marrow Cells - metabolism; Bone Marrow Cells - pathology; Cell Biology; cell division; Cell Fusion; Cell Nucleus - drug effects; Cell Nucleus - metabolism; Cell Nucleus - pathology; cell proliferation; Cells, Cultured; Crosses, Genetic; Cytokinesis - drug effects; flow cytometry; imaging; incomplete cytokinesis; 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; osteoclast; 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
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M115.677427

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.