通过促进衰老和SASP状态,SIRT6损失会导致小鼠的椎间盘退化
Pranay Ramteke1, Bahiyah Watson1, Mallory Toci1
1Department of Orthopedic Surgery, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, 19107, USA.
bioRxiv : the preprint server for biology
|September 24, 2024
概括
SIRT6蛋白对于维持椎间盘健康和预防退化至关重要. 它的损失通过损害DNA修复和自加速与衰老相关的磁盘损伤.
科学领域:
- 生物化学 生物化学
- 分子生物学分子生物学
- 老年学是一门学科.
背景情况:
- 椎间盘退化是慢性腰部和部疼痛的主要原因.
- 衰老是磁盘退化的重要危险因素.
- 已知SIRT6在衰老和骨健康中的作用,但其在椎间盘中的功能尚未被探索.
研究的目的:
- 研究SIRT6在椎间盘健康和与年龄相关的退化中的作用.
- 阐明SIRT6影响磁盘平衡的分子机制.
主要方法:
- 生成条件淘汰赛小鼠 (Acan-Cre;Sirt6-flox) 在椎间盘中删除Sirt6.
- 在12个月和24个月后对脊柱表型进行了组织学分析.
- 进行了RNA-Seq,ATAC-Seq和定量质子分析,对核肉质 (NP) 和纤维环 (AF) 组织进行了分析.
- 在体外评估了自,DNA损伤,衰老标志物 (p21,γH2AX) 和与衰老相关的分泌表型 (SASP) 因素 (IL-6,TGF-β).
主要成果:
- 磁盘中的Sirt6删除导致小鼠在24个月后出现明显的退行性表型.
- 损失SIRT6改变了基因素乙化和甲基化,影响了DNA可访问性和基因表达.
- 缺乏Sirt6的细胞显示自的减少和DNA损伤的增加.
- 损失SIRT6增加了细胞衰老和SASP负担,由增加的p21,γH2AX,IL-6和TGF-β表示.
结论:
- 在衰老期间,SIRT6在维持椎间盘健康方面发挥着至关重要的作用.
- 在磁盘细胞中,SIRT6调节DNA损伤,自和细胞衰老.
- SIRT6是治疗椎间盘退行症的潜在治疗标.
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