破骨细胞
兰克尔
骨吸收
基因敲除
化学
细胞生物学
骨重建
基因剔除小鼠
癌症研究
生物
激活剂(遗传学)
细胞凋亡
内分泌学
基因
受体
生物化学
作者
Xiu Liu,Xiaoyu Wang,Xinrong Ma,Hongyu Li,Congcong Miao,Zhenchuan Tian,Ying Hu
摘要
Gnathodiaphyseal dysplasia (GDD; OMIM#166260) is a rare skeletal genetic disorder characterized by sclerosis of tubular bones and cemento-osseous lesions in mandibles. TMEM16E/ANO5 gene mutations have been identified in patients with GDD. Here, Ano5 knockout (Ano5-/- ) mice with enhanced osteoblastogenesis were used to investigate whether Ano5 disruption affects osteoclastogenesis.The maturation of osteoclasts, formation of F-actin ring and bone resorption were detected by immunohistochemistry, TRAP, phalloidin staining and Coming Osteo assays. The expression of osteoclast-related factors was measured by qRT-PCR. Early signaling pathways were verified by western blot.Ano5-/- mice exhibited inhibitory formation of multinucleated osteoclasts with a reduction of TRAP activity. The expression of Nfatc1, c-Fos, Trap, Ctsk, Mmp9, Rank and Dc-stamp was significantly decreased in bone tissues and bone marrow-derived macrophages (BMMs) of Ano5-/- mice. Ano5-/- osteoclasts manifested disrupted actin ring and less mineral resorption. RANKL-induced early signaling pathways were suppressed in Ano5-/- osteoclasts and Ano5 knockdown RAW264.7 cells. Moreover, the inhibitory effects of NF-κB signalling pathway on osteoclastogenesis were partially attenuated with NF-κB signalling activator.Ano5 deficiency impairs osteoclastogenesis, which leads to enhanced osteogenic phenotypes mediated by bone homeostasis dysregulation.
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