内体RANKL-LGR4信号在骨质细胞分化过程中的作用
Beom Chang Kim1,2,3, Yong Jin Cho1,4, Yuria Jang1,2,5
1Laboratory of Orthopedic Research, Chosun University Hospital, Gwangju, 61452, Republic of Korea.
概括
氨酸丰富的重复含有G蛋白结合受体4 (LGR4) 信号通过其在结合RANKL后移动到内分体进行调节,影响骨质细胞形成. 这种内体体贩运是控制骨重塑的关键.
科学领域:
- 细胞生物学 细胞生物学
- 分子生物学分子生物学
- 内分泌学 在内分泌学.
背景情况:
- 骨质结晶生成对于骨质稳定至关重要,由复杂的信号通路来调节.
- 氨酸丰富的重复含有G蛋白结合受体4 (LGR4) 负面调节RANK信号级联.
- 细胞表面受体信号和内细胞贩运之间的相互作用越来越被认为是双向的.
研究的目的:
- 调查膜结合LGR4.4与内体LGR4.4之间的显著信号作用.
- 为了确定LGR4信号是否会影响骨质细胞形成过程中的RANK-RANKL信号.
- 阐明膜到内体贩运在调节LGR4信号传递中的作用.
主要方法:
- 通过CRISPR-Cas9技术创建LGR4条件淘汰 (CKO) RAW 264.7细胞.
- 产生Drg2淘汰赛 (KO) 小鼠.
- 分析LGR4内细胞分裂,内体内的局部化 (RAB5阳性) 和下游信号事件 (GSK-3β酸化,NFATC1转位).
主要成果:
- 在骨质细胞前体细胞中结合RANKL后,LGR4被内细胞化进入早期内体.
- 内化LGR4激活LGR4-RANKL信号在早期内体内.
- Lgr4 CKO细胞表现出增加的早期内体信号传递和减少的GSK-3β抑制.
- 在Lgr4 CKO细胞和Drg2 KO小鼠中,RANKL治疗增强了NFATC1核转位.
结论:
- RANKL-LGR4信号通过膜到内体的流通来动态调节.
- 对于LGR4在骨质细胞形成中的抑制作用而言,其内的局部定位至关重要.
- 这些发现揭示了一种新的机制,将受体贩运与骨重塑调节联系起来.
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