ABSTRACT

Background

Bioinformatics analysis was performed on gene expression profile microarray data to identify the key genes activated through the TNF-α/TNFR1 signaling pathway in intervertebral disc degeneration (IDD). The common differentially expressed genes (co-DEGs) were calculated in nucleus pulposus (NP) cells and annulus fibrosus (AF) cells under TNF-α treatment or TNFR1 knockdown, which reveals the potential mechanism of TNF-α involvement in IDD and may provide new therapeutic targets for IDD.

Methods

Differentially expressed genes (DEGs) in TNF-α-treated or TNFR1-knockdown NP cells and AF cells were identified. Further analysis of the gene ontology (GO), signaling pathways and interaction networks of the DEGs or co-DEGs were conducted using the Database for Annotation, Visualization and Integrated Discovery, STRING Database, and Cytoscape software. The relationship between genes and musculoskeletal diseases, including IDD, was assessed with the Comparative Toxicogenomics Database. The predicted microRNAs corresponding to the co-DEGs were also identified by microRNA Data Integration Portal.

Results

In NP cells, the DEGs (|log₂FoldChange|>2, adj.P < 0.01) were identified including 48 DEGs by TNF-α treatment and 74 DEGs by TNFR1 knockdown; in AF cells, correspondingly, 105 DEGs were identified. The co-DEGs between NP cells and AF cells were calculated including CXCL8, ICAM1, BIRC3, RELB, NFKBIA, and TNFAIP3. They may be the hub genes that were significantly associated with both NP cells and AF cells through the TNF-α/TNFR1 signaling pathway. The co-DEGs and corresponding predicted miRNAs may be potential therapeutic targets for IDD.

Conclusions

CXCL8, ICAM1, BIRC3, RELB, NFKBIA, and TNFAIP3 may have a synergistic effect on TNF-α-induced IDD development.

Abbreviations: IDD: Intervertebral disc degeneration; NP: Nucleus pulposus; AF: Annulus fibrosus; co-DEG: Common differentially expressed gene; GO: Gene Ontology; KEGG: Kyoto Encyclopedia of Genes and Genomes; PPI: Protein-protein interaction.

中文翻译：

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通过生物信息学分析识别 TNF-α/TNFR1 相关椎间盘退变的关键潜在靶点

摘要

背景

对基因表达谱微阵列数据进行生物信息学分析，以确定椎间盘退变 (IDD) 中通过 TNF-α/TNFR1 信号通路激活的关键基因。在 TNF-α 处理或 TNFR1 敲低下，计算了髓核 (NP) 细胞和纤维环 (AF) 细胞中常见的差异表达基因 (co-DEGs)，揭示了 TNF-α 参与 IDD 的潜在机制，并可能提供IDD 的新治疗靶点。

方法

鉴定了 TNF-α 处理或 TNFR1 敲低 NP 细胞和 AF 细胞中的差异表达基因 (DEG)。使用注释、可视化和集成发现数据库、STRING 数据库和 Cytoscape 软件对 DEG 或协同 DEG 的基因本体 (GO)、信号通路和相互作用网络进行了进一步分析。使用比较毒物基因组学数据库评估了基因与包括 IDD 在内的肌肉骨骼疾病之间的关系。对应于 co-DEG 的预测 microRNAs 也由 microRNA Data Integration Portal 鉴定。

结果

在 NP 细胞中，鉴定出 DEGs (|log ₂ FoldChange|>2, adj.P < 0.01)，其中 48 个经 TNF-α 处理，74 个经 TNFR1 敲低处理；在 AF 细胞中，相应地鉴定出 105 个 DEG。计算了 NP 细胞和 AF 细胞之间的 co-DEG，包括 CXCL8、ICAM1、BIRC3、RELB、NFKBIA 和 TNFAIP3。它们可能是通过 TNF-α/TNFR1 信号通路与 NP 细胞和 AF 细胞显着相关的中枢基因。co-DEGs 和相应的预测 miRNAs 可能是 IDD 的潜在治疗靶点。

结论

CXCL8、ICAM1、BIRC3、RELB、NFKBIA 和 TNFAIP3 可能对 TNF-α 诱导的 IDD 发展具有协同作用。

缩写： IDD：椎间盘退变；NP：髓核；AF：纤维环；co-DEG：常见的差异表达基因；GO：基因本体；KEGG：京都基因和基因组百科全书；PPI：蛋白质-蛋白质相互作用。