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NSC23766 通过抑制 Rac1 活性来防止软骨终板退变，其作用机制与 Wnt/β-catenin 信号通路有关。

Inhibition of Rac1 activity by NSC23766 prevents cartilage endplate degeneration via Wnt/β-catenin pathway.

机构信息

Department of Orthopaedic surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.

Zhejiang Provincial Key Laboratory of Orthopaedics, Wenzhou, China.

出版信息

J Cell Mol Med. 2020 Mar;24(6):3582-3592. doi: 10.1111/jcmm.15049. Epub 2020 Feb 10.

DOI:10.1111/jcmm.15049
PMID:32040269
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7131937/
Abstract

Cartilage endplate (CEP) degeneration has been considered as one of important factors related to intervertebral disc degeneration (IVDD). Previous researches have showed that Rac1 played a pivotal role in chondrocyte differentiation. However, the effect of Rac1 during the process of CEP degeneration remains unclear. Herein, we explored the effect of Rac1 on CEP degeneration and elucidated the underlying molecular mechanism. We found expression of Rac1-GTP increased in human-degenerated CEP tissue and IL-1β-stimulated rat endplate chondrocytes (EPCs). Our study revealed that Rac1 inhibitor NSC23766 treatment promoted the expression of collagen II, aggrecan and Sox-9, and decreased the expression of ADTAMTS5 and MMP13 in IL-1β-stimulated rat EPCs. Moreover, we also found that NSC23766 could suppress the activation of Wnt/β-catenin pathway, suggesting that the beneficial effects of Rac1 inhibition in EPCs are mediated through the Wnt/β-catenin signalling. Besides, puncture-induced rats models showed that NSC23766 played a protective role on CEP and disc degeneration. Collectively, these findings demonstrated that Rac1 inhibition delayed the EPCs degeneration and its potential mechanism may be associated with Wnt/β-catenin pathway regulation, which may help us better understand the association between Rac1 and CEP degeneration and provide a promising strategy for delaying the progression of IVDD.

摘要

软骨终板（CEP）退变被认为是与椎间盘退变（IVDD）相关的重要因素之一。先前的研究表明，Rac1 在软骨细胞分化中发挥着关键作用。然而，Rac1 在 CEP 退变过程中的作用尚不清楚。在此，我们探讨了 Rac1 对 CEP 退变的影响，并阐明了其潜在的分子机制。我们发现 Rac1-GTP 的表达在人退变的 CEP 组织和 IL-1β 刺激的大鼠终板软骨细胞（EPCs）中增加。我们的研究表明，Rac1 抑制剂 NSC23766 处理促进了 IL-1β 刺激的大鼠 EPCs 中胶原 II、聚集蛋白聚糖和 Sox-9 的表达，并降低了 ADTAMTS5 和 MMP13 的表达。此外，我们还发现 NSC23766 可以抑制 Wnt/β-catenin 通路的激活，表明 Rac1 抑制在 EPCs 中的有益作用是通过 Wnt/β-catenin 信号转导介导的。此外，穿刺诱导的大鼠模型表明，NSC23766 对 CEP 和椎间盘退变具有保护作用。综上所述，这些发现表明 Rac1 抑制延缓了 EPCs 的退变，其潜在机制可能与 Wnt/β-catenin 通路的调节有关，这可能有助于我们更好地理解 Rac1 与 CEP 退变的关系，并为延缓 IVDD 的进展提供一种有前途的策略。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5700/7131937/6b77052f5f71/JCMM-24-3582-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5700/7131937/a10f573c2110/JCMM-24-3582-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5700/7131937/5544c28954f9/JCMM-24-3582-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5700/7131937/cca6ccc00685/JCMM-24-3582-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5700/7131937/86a45ecdfda3/JCMM-24-3582-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5700/7131937/b3a30a53c3ad/JCMM-24-3582-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5700/7131937/ef047ff4242b/JCMM-24-3582-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5700/7131937/6b77052f5f71/JCMM-24-3582-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5700/7131937/a10f573c2110/JCMM-24-3582-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5700/7131937/5544c28954f9/JCMM-24-3582-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5700/7131937/cca6ccc00685/JCMM-24-3582-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5700/7131937/86a45ecdfda3/JCMM-24-3582-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5700/7131937/b3a30a53c3ad/JCMM-24-3582-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5700/7131937/ef047ff4242b/JCMM-24-3582-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5700/7131937/6b77052f5f71/JCMM-24-3582-g007.jpg

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