TDP-43 基因表达对缺血缺氧应激依赖性炎症因子及 JNK 和 p38 MAPK 信号通路的作用机制。
The mechanism of TDP-43 gene expression on inflammatory factors and the JNK and p38 MAPK signalling pathways in ischaemic hypoxic stress dependence.
机构信息
Department of Orthopedic Surgery, Guangzhou Hospital of Integrated Traditional and Western Medicine, Guangzhou, China.
出版信息
Int Wound J. 2019 Jun;16(3):724-729. doi: 10.1111/iwj.13087. Epub 2019 Feb 19.
In this study, the mechanism of TDP-43 gene expression on inflammatory factors and Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) signalling pathways in ischaemic hypoxic stress dependence was investigated. Sixty SD rats were selected and divided into the control group, the osteoarthritis (OA) model group, and the TDP-43-mMSCs+OA group. In the OA model group and the TDP-43-mMSCs+OA group, OA was established by collagenase injection. Western blotting assays were used to detect the expression of TDP-43 in cartilage tissues of each rat. The secretion of tumour necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) in the serum of rats was determined by enzyme-linked immunosorbent assay (ELISA). The formation of cytoplasmic stress granules (SGs) and the expression of receptor for activated c-kinase 1 (RACK1) were detected by Western blotting assays in each group of rats. The expression of MTK1 and MAPKKK phosphorylation and changes in the JNK and p38 MAPK signalling pathways were detected by Western blotting assays. Compared with the control group, the expression of TDP-43 in the cartilage tissue of rats in the OA model group was significantly decreased. The expression of TDP-43 in the cartilage tissue of rats in the TDP-43-mMSCs+OA group was significantly higher than that of the control group and the OA model group, which indicates that TDP-43-mMSC transplantation was successful. Enzyme-linked immunosorbent assay results showed that the plasma TNF-α and IL-1β levels in the OA model group were significantly increased (P < 0.01) when compared with the control group. However, the secretion of TNF-α and IL-1β in the serum of the TDP-43-mMSCs+OA group was significantly lower than that of the model group (P < 0.01) but still higher than the control group. This indicates that overexpression of TDP-43 reduces the inflammatory response induced by OA. Western blotting assays showed that the amount of cytoplasmic SGs in the cartilage tissue of rats in the OA model group was significantly decreased when compared with the control group. The amount of SGs in the cartilage of rats in the TDP-43-mMSCs+OA group was significantly higher than that of the model group. The expression of RACK1 in the cartilage tissue of rats in the OA model group was significantly higher than that of the control group. Overexpression of the TDP-43 gene can interfere with the secretion of inflammatory factors and inhibit the activation of the JNK and p38 MAPK signalling pathways by ischaemic hypoxia stress. Thus, the molecular mechanism of chondrocytopathic lesions was reversed, which provided a new theoretical basis for the treatment of OA.
在这项研究中，探讨了 TDP-43 基因表达对缺血缺氧应激依赖性炎症因子和 Jun N-末端激酶（JNK）和 p38 丝裂原活化蛋白激酶（MAPK）信号通路的影响。选择 60 只 SD 大鼠，分为对照组、骨关节炎（OA）模型组和 TDP-43-mMSCs+OA 组。在 OA 模型组和 TDP-43-mMSCs+OA 组中，通过胶原酶注射建立 OA。Western blot 检测各组大鼠软骨组织中 TDP-43 的表达。酶联免疫吸附试验（ELISA）检测各组大鼠血清中肿瘤坏死因子-α（TNF-α）和白细胞介素-1β（IL-1β）的分泌。Western blot 检测各组大鼠细胞质应激颗粒（SGs）的形成和受体激活 c-激酶 1（RACK1）的表达。Western blot 检测 MTK1 和 MAPKKK 磷酸化表达以及 JNK 和 p38 MAPK 信号通路的变化。与对照组相比，OA 模型组大鼠软骨组织中 TDP-43 的表达明显降低。TDP-43-mMSCs+OA 组大鼠软骨组织中 TDP-43 的表达明显高于对照组和 OA 模型组，表明 TDP-43-mMSC 移植成功。酶联免疫吸附试验结果显示，OA 模型组大鼠血浆 TNF-α和 IL-1β水平明显升高（P<0.01），与对照组相比。然而，TDP-43-mMSCs+OA 组大鼠血清中 TNF-α和 IL-1β的分泌明显低于模型组（P<0.01），但仍高于对照组。这表明 TDP-43 的过表达可减轻 OA 诱导的炎症反应。Western blot 检测结果显示，OA 模型组大鼠软骨组织中细胞质 SGs 的含量明显低于对照组。TDP-43-mMSCs+OA 组大鼠软骨中 SGs 的含量明显高于模型组。OA 模型组大鼠软骨组织中 RACK1 的表达明显高于对照组。TDP-43 基因的过表达可干扰缺血缺氧应激诱导的炎症因子分泌，并抑制 JNK 和 p38 MAPK 信号通路的激活。因此，逆转了软骨细胞病变的分子机制，为 OA 的治疗提供了新的理论依据。
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