Locally Produced IGF-1 Promotes Hypertrophy of the Ligamentum Flavum via the mTORC1 Signaling Pathway
Locally Produced IGF-1 Promotes Hypertrophy of the Ligamentum Flavum via the mTORC1 Signaling Pathway
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本地产生的 IGF-1 通过 mTORC1 信号通路促进黄韧带肥大
DOI：
10.1159/000491729
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发表时间：
2018
影响因子：
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通讯作者：
Wang Liang
中科院分区：
文献类型：
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作者：
Yan Bin;Huang Minjun;Zeng Canjun;Yao Na;Zhang Jie;Yan Bo;Jiang Huaji;Tian Xinggui;Ao Xiang;Zhao Huiyu;Zhou Wen;Chu Jun;Wang Liping;Xian Cory J.;Zhang Zhongmin;Wang Liang
背景/目的：腰椎椎管狭窄是一种被称为腰椎管狭窄症（LSS）的病症，在老年人中是一个高发病率问题。腰椎管狭窄症通常由黄韧带肥厚（HLF）引起。先前研究表明，黄韧带（LF）纤维化在很大程度上导致了黄韧带肥厚。然而，其潜在的发病机制仍不明确。已知胰岛素样生长因子 - 1（IGF - 1）与多种组织的纤维化密切相关。不过，目前关于IGF - 1在黄韧带肥厚方面的研究较少。在本研究中，我们探究了IGF - 1在黄韧带肥厚中的作用及其潜在的分子作用机制。
方法：首先，通过免疫组织化学和蛋白质免疫印迹法检测LSS患者和非LSS患者黄韧带组织中IGF - 1、IGF - 1受体磷酸化水平（pIGF - 1R）、蛋白激酶B磷酸化水平（pAKT）、S6蛋白磷酸化水平（pS6）、Ⅰ型胶原蛋白和Ⅲ型胶原蛋白的表达水平。其次，从黄韧带厚度正常的成年人中分离出原代黄韧带细胞，用不同浓度的IGF - 1进行培养，同时设置添加或不添加NVP - AEW541/雷帕霉素的组别。
结果：结果显示，LSS组中IGF - 1、pIGF - 1R、pAKT、pS6、Ⅰ型胶原蛋白和Ⅲ型胶原蛋白的蛋白表达水平显著高于非LSS组。同时，IGF - 1处理后的黄韧带细胞中，pIGF - 1R、pAKT、pS6、Ⅰ型胶原蛋白和Ⅲ型胶原蛋白的蛋白表达显著增强，而NVP - AEW541可显著阻断这种增强作用。此外，雷帕霉素可阻断pS6、Ⅰ型胶原蛋白和Ⅲ型胶原蛋白的蛋白表达。
结论：增强的IGF - 1通过mTORC1信号通路促进Ⅰ型胶原蛋白和Ⅲ型胶原蛋白的合成，最终导致黄韧带肥厚。（C）2018作者。由巴塞尔S. Karger AG出版
Background/Aims: Narrowing of the lumbar spinal canal is a condition called lumbar spinal stenosis (LSS) and is a high-morbidity problem in the elderly. LSS is commonly caused by hypertrophy of the ligamentum flavum (HLF). Previous studies showed that fibrosis of the ligamentum flavum (LF) largely contributed to HLF. However, the underlying pathomechanism remains unclear. Insulin-like growth factor-1 (IGF-1) is known to have an intimate relationship with fibrosis in various tissues. Nevertheless, currently, there are few studies regarding IGF-1 in HLF. In this study, we investigated the role of IGF-1 in HLF and its potential molecular mechanism of action. Methods: First, the IGF-1, phosphorylation of IGF-1 receptor (pIGF-1R), phosphorylation of AKT (pAKT), phosphorylation of S6(pS6), collagen I and collagen III expression levels were examined via immunohistochemistry and Western blotting in LF tissues from patients with LSS or Non-LSS. Second, primary LF cells were isolated from adults with a normal LF thickness and were cultured with different concentrations of IGF-1 with or without NVP-AEW541/rapamycin. Results: The results showed that IGF-1, pIGF-1R, pAKT, pS6, collagen I and collagen III protein expression in the LSS group was significantly higher than that in the Non-LSS group. Meanwhile, pIGF-1R, pAKT, pS6, collagen I and collagen III protein expression was significantly enhanced in LF cells after IGF-1 exposure, which can be notably blocked by NVP-AEW541. In addition, pS6, collagen I and collagen III protein expression was blocked by rapamycin. Conclusions: Enhanced IGF-1 promotes the synthesis of collagen I and collagen III via the mTORC1 signaling pathway, which eventually contributes to hypertrophy of the ligamentum flavum.