The small compound, TD-198946, protects against intervertebral degeneration by enhancing glycosaminoglycan synthesis in nucleus pulposus cells
The small compound, TD-198946, protects against intervertebral degeneration by enhancing glycosaminoglycan synthesis in nucleus pulposus cells
复制标题
小分子化合物TD-198946通过增强髓核细胞中的糖胺聚糖合成来防止椎间变性
DOI：
10.1038/s41598-020-71193-6
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发表时间：
2020-08-25
影响因子：
4.6
通讯作者：
Yoshikawa, Hideki
中科院分区：
文献类型：
--
作者：
Kushioka, Junichi;Kaito, Takashi;Yoshikawa, Hideki
髓核（NP）退变可能是椎间盘退变（IDD）的触发因素。最近的一项药物筛选研究显示，噻吩茚唑衍生物TD-198946是一种治疗骨关节炎的新药。由于关节软骨和椎间盘在环境和功能上的相似性，TD-198946有望预防IDD。在此，我们试图评估TD-198946对IDD的影响。TD-198946增强小鼠NP细胞和人NP细胞（hNPCs）中糖胺聚糖（GAG）的产生及相关基因的表达。此外，京都基因和基因组百科全书对hNPCs的mRNA序列进行通路分析表明，TD-198946的作用机制主要通过磷酸肌醇3-激酶(PI3K)/Akt信号通路发生。Akt抑制剂抑制了TD-198946诱导的GAG生成增强。采用小鼠尾盘穿刺模型，观察TD-198946在两个不同时间点（即刻治疗模型，穿刺后即刻；潜伏治疗模型，穿刺后2周）对IDD的影响。在这两个时间点，TD-198946防止了阀瓣高度的损失。组织学分析也显示了NP结构的保存。TD-198946通过PI3K/Akt信号通路增强GAG的产生，显示出治疗IDD的作用。
Degeneration of the nucleus pulposus (NP) might serve as a trigger for intervertebral disc degeneration (IDD). A recent drug screening study revealed that the thienoindazole derivative, TD-198946, is a novel drug for the treatment of osteoarthritis. Because of the environmental and functional similarities between articular cartilage and intervertebral disc, TD-198946 is expected to prevent IDD. Herein, we sought to evaluate the effects of TD-198946 on IDD. TD-198946 enhanced glycosaminoglycan (GAG) production and the related genes in mouse NP cells and human NP cells (hNPCs). Further, Kyoto Encyclopedia of Genes and Genomes pathway analysis using the mRNA sequence of hNPCs suggested that the mechanism of action of TD-198946 primarily occurred via the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway. The Akt inhibitor suppressed the enhancement of GAG production induced by TD-198946. The effects of TD-198946 on IDD at two different time points (immediate treatment model, immediately after the puncture; latent treatment model, 2 weeks after the puncture) were investigated using a mouse tail-disc puncture model. At both time points, TD-198946 prevented a loss in disc height. Histological analysis also demonstrated the preservation of the NP structures. TD-198946 exhibited therapeutic effects on IDD by enhancing GAG production via PI3K/Akt signaling.