Involvement of Receptor Activator of Nuclear Factor-κB Ligand (RANKL)-induced Incomplete Cytokinesis in the Polyploidization of Osteoclasts.
Involvement of Receptor Activator of Nuclear Factor-κB Ligand (RANKL)-induced Incomplete Cytokinesis in the Polyploidization of Osteoclasts.
复制标题
DOI：
10.1074/jbc.m115.677427
复制
发表时间：
2016-02-12
期刊：
影响因子：
--
通讯作者：
Choi Y
中科院分区：
文献类型：
--
作者：
Takegahara N;Kim H;Mizuno H;Sakaue-Sawano A;Miyawaki A;Tomura M;Kanagawa O;Ishii M;Choi Y
破骨细胞是专门吸收骨的多倍体细胞。在核因子-κB配体受体激活剂（RANKL）的刺激下，髓细胞前体主要通过细胞融合成为多倍体。破骨细胞的多倍体化是其骨吸收活性所必需的，但多倍体化的控制机制仍有待确定。在这里，我们证明除了细胞融合，不完全的细胞分裂也在破骨细胞多倍体化中起作用。在体外培养的表达荧光泛素细胞周期指标（Fucci）的小鼠破骨细胞中，RANKL通过不完全细胞分裂和细胞融合诱导多倍体。由不完全细胞质分裂产生的多倍体细胞具有随后进行细胞融合的潜力。在体内破骨细胞中也观察到核多倍体，表明细胞分裂不完全参与了生理性多倍体的发生。此外，抑制Akt可减少rankl诱导的不完全细胞分裂，导致多核破骨细胞形成受损。综上所述，这些结果表明rankl诱导的不完全细胞分裂通过Akt激活促进破骨细胞的多倍体化。
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.