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骨质发育因子体中的IRE1信号增强了β-catenin活性和生理骨积累
Lakshmi D Kolora1, Christian Melendez-Suchi2, Veronica Butler1
1Department of Orthopedics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
概括
展开的蛋白质响应 (UPR) 传感器 IRE1α 对骨健康至关重要. 在骨质母细胞中删除IRE1α通过损害骨质生殖器功能和β-catenin活性来降低骨质量和强度.
科学领域:
- 骨生物学和内质网膜压力.
- 研究未折叠蛋白响应 (UPR) 在骨质生成中的作用.
背景情况:
- 细胞内膜网膜 (ER) 在骨质生成过程中管理蛋白质折叠.
- UPR在骨质细胞分化中的作用是复杂的,根据大小和持续时间的影响有所不同.
- 虽然UPR传感器 (IRE1,PERK,ATF6) 与骨生物学有关,但它们在骨质细胞分化中的体内作用尚不清楚.
研究的目的:
- 系统地研究IRE1α,PERK和ATF6对骨质细胞分化和骨功能的体内贡献.
- 确定IRE1α在骨质生殖器增殖,分化和骨积累中的特定作用.
主要方法:
- 通过使用Osx1-Cre.6,在骨质细胞系中产生具有针对性删除Ire1α,Perk或Atf6的小鼠.
- 评估骨表型,包括骨质和强度.
- 对主要骨髓培养物进行分析,以了解骨质生殖器的扩散,性酸酶的活性和生存率.
- RNA测序 (RNA-seq) 用于分析基因表达变化和预测途径参与.
- 对骨质原生动物中β-catenin活性的研究.
主要成果:
- 骨质细胞特定的Ire1α缺失导致骨质细胞数量,骨质量和骨强度显著降低.
- 在骨质发育因子中Ire1α的丧失影响了增殖,性酸酶活性和存活率.
- RNA-seq数据表明骨质基因表达被抑制,并在Ire1α删除后预测降低β-catenin活性.
- 发现IRE1α可以增强骨质生殖器中β-catenin的核转位和转录活性.
- 在骨质细胞系中删除Perk或Atf6并没有影响骨质量或强度.
结论:
- IRE1α是一种UPR传感器,在促进生理骨积累方面发挥着至关重要的作用.
- IRE1α支持骨质细胞的分化和功能,部分是通过增强骨质生成器中的β-catenin活性.
- 与IRE1α不同,PERK和ATF6在这种情况下似乎并不必不可少,以保持骨质或强度.
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