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准VGLL4可以维持细胞外矩阵的恒温,并减轻骨关节炎在临床前模型

Jinlong Suo¹, Duo Wang², Jinghui Wang²

¹Institute of Microsurgery on Extremities, Department of Orthopedic Surgery, Shanghai Sixth People's Hospital Affiliated with Shanghai Jiao Tong University School of Medicine, Shanghai, China. suojinlong2015@sibcb.ac.cn.

Nature communications

|October 22, 2025

概括

VGLL4对于维持软骨健康和细胞外矩阵恒温至关重要. 恢复VGLL4或SMAD3水平可以治疗骨关节炎,强调VGLL4复合体作为治疗点.

科学领域:

生物化学生物化学
细胞生物学细胞生物学
整形外科整形外科整形外科

背景情况:

细胞外矩阵 (ECM) 稳态对于质软骨的完整性至关重要.
控制冠状细胞中ECM稳态的精确机制在很大程度上是未知的.
软骨细胞中的VGLL4表达随着软骨损伤和衰老而降低.

研究的目的:

阐明VGLL4在维持冠状细胞ECM平衡中的作用.
调查VGLL4介导的ECM调控背后的分子机制.
探索针对骨关节炎的VGLL4复合物的治疗潜力.

主要方法:

单细胞测序来分析VGLL4表达.
基因操纵 (Col2-CreERT2; Vgll4^fl/fl小鼠) 来研究VGLL4缺乏症.
骨关节炎的手术诱导 (中间半月的不稳定).
对VGLL4-TEAD-SMAD3复合物的分子相互作用研究 (键,疏水接触,π堆叠).
在体内使用腺相关病毒 (AAV) 载体进行基因治疗.

主要成果:

冠状细胞中的VGLL4缺乏导致原蛋白和弹性质形成受损,ECM失序,骨关节炎的发展.
VGLL4-TEAD-SMAD3复合体对于ECM平衡至关重要,已确定了特定的氨基酸相互作用.
在小鼠的关节内输送编码SMAD3或VGLL4的AAV显著改善了骨关节炎病理.
当使用缺乏相互作用的VGLL4或SMAD3突变体时,治疗疗效就会丧失.

结论:

VGLL4是红细胞中ECM稳态的关键调节者.
在维护软骨完整性方面,VGLL4-TEAD-SMAD3复合体起着至关重要的作用.
针对VGLL4复合体,特别是SMAD3或VGLL4,为骨关节炎和软骨纤维化提供了一个有前途的治疗策略.

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