Zhao Yongzhao, Xiang Qian, Jiang Shuai, Lin Jialiang, Li Weishi
Department of Orthopaedics Peking University Third Hospital Beijing China.
Beijing Key Laboratory of Spinal Disease Research Beijing China.
JOR Spine. 2024 Jul 15;7(3):e1357. doi: 10.1002/jsp2.1357. eCollection 2024 Sep.
The ossification of the ligamentum flavum (OLF) is one of the major causes of thoracic myelopathy. Previous studies indicated there might be a potential link between metabolic disorder and pathogenesis of OLF. The aim of this study was to determine the potential role of metabolic disorder in the pathogenesis of OLF using the strict bioinformatic workflow for metabolism-related genes and experimental validation.
A series of bioinformatic approaches based on metabolism-related genes were conducted to compare the metabolism score between OLF tissues and normal ligamentum flavum (LF) tissues using the single sample gene set enrichment analysis. The OLF-related and metabolism-related differentially expressed genes (OMDEGs) were screened out, and the biological functions of OMDEGs were explored, including the Gene Ontology enrichment analysis, Kyoto Encyclopedia of Genes and Genomes enrichment analysis, and protein-protein interaction. The competing endogenous RNA (ceRNA) network based on pairs of miRNA-hub OMDEGs was constructed. The correlation analysis was conducted to explore the potential relationship between metabolic disorder and immunity abnormality in OLF. In the end, the cell experiments were performed to validate the roles of GBE1 and TNF-α in the osteogenic differentiation of LF cells.
There was a significant difference of metabolism score between OLF tissues and normal LF tissues. Forty-nine OMDEGs were screened out and their biological functions were determined. The ceRNA network containing three hub OMDEGs and five differentially expressed miRNAs (DEmiRNAs) was built. The correlation analysis between hub OMDEGs and OLF-related infiltrating immune cells indicated that metabolic disorder might contribute to the OLF via altering the local immune status of LF tissues. The cell experiments determined the important roles of GBE1 expression and TNF-α in the osteogenic differentiation of LF cells.
This research, for the first time, preliminarily illustrated the vital role of metabolic disorder in the pathogenesis of OLF using strict bioinformatic algorithms and experimental validation for metabolism-related genes, which could provide new insights for investigating disease mechanism and screening effective therapeutic targets of OLF in the future.
黄韧带骨化（OLF）是胸段脊髓病的主要病因之一。既往研究表明，代谢紊乱与OLF的发病机制之间可能存在潜在联系。本研究的目的是通过针对代谢相关基因的严格生物信息学流程和实验验证，确定代谢紊乱在OLF发病机制中的潜在作用。
采用基于代谢相关基因的一系列生物信息学方法，使用单样本基因集富集分析比较OLF组织与正常黄韧带（LF）组织之间的代谢评分。筛选出OLF相关和代谢相关的差异表达基因（OMDEGs），并探讨OMDEGs的生物学功能，包括基因本体富集分析、京都基因与基因组百科全书富集分析和蛋白质-蛋白质相互作用。构建基于miRNA-枢纽OMDEGs对的竞争性内源性RNA（ceRNA）网络。进行相关性分析，以探讨OLF中代谢紊乱与免疫异常之间的潜在关系。最后，进行细胞实验以验证GBE1和TNF-α在LF细胞成骨分化中的作用。
OLF组织与正常LF组织之间的代谢评分存在显著差异。筛选出49个OMDEGs并确定了它们的生物学功能。构建了包含3个枢纽OMDEGs和5个差异表达miRNA（DEmiRNAs）的ceRNA网络。枢纽OMDEGs与OLF相关浸润免疫细胞之间的相关性分析表明，代谢紊乱可能通过改变LF组织的局部免疫状态导致OLF。细胞实验确定了GBE1表达和TNF-α在LF细胞成骨分化中的重要作用。
本研究首次使用针对代谢相关基因的严格生物信息学算法和实验验证，初步阐明了代谢紊乱在OLF发病机制中的重要作用，可为未来研究OLF的发病机制和筛选有效的治疗靶点提供新的见解。
