Lumbar spinal canal stenosis is primarily caused by ligamentum flavum hypertrophy (LFH), which is a significant pathological factor. Nevertheless, the precise molecular basis for the development of LFH remains uncertain. The current investigation observed a notable increase in thrombospondin-1 (THBS1) expression in LFH through proteomics analysis and single-cell RNA-sequencing analysis of clinical ligamentum flavum specimens. In laboratory experiments, it was demonstrated that THBS1 triggered the activation of Smad3 signaling induced by transforming growth factor β1 (TGFβ1), leading to the subsequent enhancement of COL1A2 and α-SMA, which are fibrosis markers. Furthermore, experiments conducted on a bipedal standing mouse model revealed that THBS1 played a crucial role in the development of LFH. Sestrin2 (SESN2) acted as a stress-responsive protein that suppressed the expression of THBS1, thus averting the progression of fibrosis in ligamentum flavum (LF) cells. To summarize, these results indicate that mechanical overloading causes an increase in THBS1 production, which triggers the TGFβ1/Smad3 signaling pathway and ultimately results in the development of LFH. Targeting the suppression of THBS1 expression may present a novel approach for the treatment of LFH.

腰椎管狭窄主要是由黄韧带肥厚（LFH）引起的，是重要的病理因素。然而，LFH 发展的确切分子基础仍不确定。目前的研究通过对临床黄韧带标本的蛋白质组学分析和单细胞 RNA 测序分析，观察到 LFH 中血小板反应蛋白-1 (THBS1) 表达显着增加。实验室实验表明，THBS1 触发转化生长因子 β1 (TGFβ1) 诱导的 Smad3 信号激活，导致纤维化标志物 COL1A2 和 α-SMA 随后增强。此外，在双足站立小鼠模型上进行的实验表明，THBS1 在 LFH 的发展中发挥着至关重要的作用。 Sestrin2 (SESN2) 作为一种应激反应蛋白，可抑制 THBS1 的表达，从而避免黄韧带 (LF) 细胞纤维化的进展。总而言之，这些结果表明机械超负荷会导致 THBS1 产生增加，从而触发 TGFβ1/Smad3 信号通路，最终导致 LFH 的发生。以抑制 THBS1 表达为目标可能为治疗 LFH 提供一种新方法。