Experimental confirmation and bioinformatics reveal biomarkers of immune system infiltration and hypertrophy ligamentum flavum

IF 3.4 3区医学 Q1 ORTHOPEDICS

JOR Spine Pub Date : 2024-07-25 DOI:10.1002/jsp2.1354

Fei Liu, Min Zhong, Lei Yang, Chao Song, Chaoqi Chen, Zhiwei Xu, Chi Zhang, Zhifa Li, Xiaofei Wu, Chen Jiang, Feng Chen, Qian Yan

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Abstract

Background

Hypertrophy ligamentum flavum is a prevalent chronic spinal condition that affects middle-aged and older adults. However, the molecular pathways behind this disease are not well comprehended.

Objective

The objective of this work is to implement bioinformatics techniques in order to identify crucial biological markers and immune infiltration that are linked to hypertrophy ligamentum flavum. Further, the study aims to experimentally confirm the molecular mechanisms that underlie the hypertrophy ligamentum flavum.

Methods

The corresponding gene expression profiles (GSE113212) were selected from a comprehensive gene expression database. The gene dataset for hypertrophy ligamentum flavum was acquired from GeneCards. A network of interactions between proteins was created, and an analysis of functional enrichment was conducted using the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) databases. An study of hub genes was performed to evaluate the infiltration of immune cells in patient samples compared to tissues from the control group. Finally, samples of the ligamentum flavum were taken with the purpose of validating the expression of important genes in a clinical setting.

Results

Overall, 27 hub genes that were differently expressed were found through molecular biology. The hub genes were found to be enriched in immune response, chemokine-mediated signaling pathways, inflammation, ossification, and fibrosis processes, as demonstrated by GO and KEGG studies. The main signaling pathways involved include the TNF signaling pathway, cytokine–cytokine receptor interaction, and TGF-β signaling pathway. An examination of immunocell infiltration showed notable disparities in B cells (naïve and memory) and activated T cells (CD4 memory) between patients with hypertrophic ligamentum flavum and the control group of healthy individuals. The in vitro validation revealed markedly elevated levels of ossification and fibrosis-related components in the hypertrophy ligamentum flavum group, as compared to the normal group.

Conclusion

The TGF-β signaling pathway, TNF signaling pathway, and related hub genes play crucial roles in the progression of ligamentum flavum hypertrophic. Our study may guide future research on fibrosis of the ligamentum flavum.

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实验证实和生物信息学揭示了免疫系统浸润和黄韧带肥厚的生物标志物。

背景：黄韧带肥厚症是一种常见的慢性脊柱疾病，多发于中老年人。然而，人们对这种疾病背后的分子途径还不甚了解：这项工作的目的是采用生物信息学技术，以确定与黄韧带肥厚有关的关键生物标记和免疫浸润。此外，该研究还旨在通过实验证实黄韧带肥厚的分子机制：方法：从全面的基因表达数据库中筛选出相应的基因表达谱（GSE113212）。黄韧带肥厚的基因数据集来自 GeneCards。建立了蛋白质之间的相互作用网络，并利用京都基因和基因组百科全书（KEGG）和基因本体（GO）数据库进行了功能富集分析。对枢纽基因进行了研究，以评估与对照组组织相比，患者样本中免疫细胞的浸润情况。最后，还采集了黄韧带样本，以验证重要基因在临床环境中的表达情况：结果：通过分子生物学研究，共发现了 27 个表达不同的中心基因。通过 GO 和 KEGG 研究发现，这些中心基因主要集中在免疫反应、趋化因子介导的信号通路、炎症、骨化和纤维化过程中。涉及的主要信号通路包括 TNF 信号通路、细胞因子-细胞因子受体相互作用和 TGF-β 信号通路。对免疫细胞浸润的研究显示，肥厚性黄韧带患者与健康人对照组之间在 B 细胞（幼稚细胞和记忆细胞）和活化 T 细胞（CD4 记忆细胞）方面存在明显差异。体外验证显示，与正常组相比，黄韧带肥厚组的骨化和纤维化相关成分水平明显升高：结论：TGF-β信号通路、TNF信号通路及相关枢纽基因在黄韧带肥大症的进展中起着关键作用。我们的研究可为今后有关黄韧带纤维化的研究提供指导。

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