载脂蛋白 D 作为潜在生物标志物及通过加权基因共表达网络分析构建与骨关节炎相关的转录调控-免疫网络。
Apolipoprotein D as a Potential Biomarker and Construction of a Transcriptional Regulatory-Immune Network Associated with Osteoarthritis by Weighted Gene Coexpression Network Analysis.
机构信息
Department of Orthopedics Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China.
Department of Orthopedics Surgery, The First Medical Center, Chinese PLA General Hospital, Beijing, China.
出版信息
Cartilage. 2021 Dec;13(1_suppl):1702S-1717S. doi: 10.1177/19476035211053824. Epub 2021 Oct 31.
OBJECTIVE
Synovial inflammation influences the progression of osteoarthritis (OA). Herein, we aimed to identify potential biomarkers and analyze transcriptional regulatory-immune mechanism of synovitis in OA using weighted gene coexpression network analysis (WGCNA).
DESIGN
A data set of OA synovium samples (GSE55235) was analyzed based on WGCNA. The most significant module with OA was identified and function annotation of the module was performed, following which the hub genes of the module were identified using Pearson correlation and a protein-protein interaction network was constructed. A transcriptional regulatory network of hub genes was constructed using the TRRUST database. The immune cell infiltration of OA samples was evaluated using the single-sample Gene Set Enrichment Analysis (ssGSEA) method. The hub genes coexpressed in multiple tissues were then screened out using data sets of synovium, cartilage, chondrocyte, subchondral bone, and synovial fluid samples. Finally, transcriptional factors and coexpressed hub genes were validated via experiments.
RESULTS
The turquoise module of GSE55235 was identified via WGCNA. Functional annotation analysis showed that "mineral absorption" and "FoxO signaling pathway" were mostly enriched in the module. JUN, EGR1, FOSB, and KLF4 acted as central nodes in protein-protein interaction network and transcription factors to connect several target genes. "Activated B cell," "activated CD4T cell," "eosinophil," "neutrophil," and "type 17 T helper cell" showed high immune infiltration, while FOSB, KLF6, and MYBL2 showed significant negative correlation with type 17 T helper cell.
CONCLUSIONS
Our results suggest that the expression level of apolipoprotein D (APOD) was correlated with OA. Furthermore, transcriptional regulatory-immune network was constructed, which may contribute to OA therapy.
目的
滑膜炎症影响骨关节炎（OA）的进展。在此，我们旨在通过加权基因共表达网络分析（WGCNA）鉴定 OA 滑膜炎症的潜在生物标志物并分析其转录调控-免疫机制。
设计
基于 WGCNA 分析 OA 滑膜样本数据集（GSE55235）。鉴定与 OA 最显著相关的模块并进行模块功能注释，随后使用 Pearson 相关性鉴定模块的枢纽基因，并构建蛋白质-蛋白质相互作用网络。使用 TRRUST 数据库构建枢纽基因的转录调控网络。使用单样本基因集富集分析（ssGSEA）方法评估 OA 样本的免疫细胞浸润情况。然后使用滑膜、软骨、软骨细胞、软骨下骨和滑液样本数据集筛选出在多个组织中共表达的枢纽基因。最后，通过实验验证转录因子和共表达的枢纽基因。
结果
通过 WGCNA 鉴定出 GSE55235 的绿松石模块。功能注释分析表明，该模块主要富集了“矿物质吸收”和“FoxO 信号通路”。JUN、EGR1、FOSB 和 KLF4 作为蛋白-蛋白相互作用网络和转录因子的中心节点，连接了几个靶基因。“活化 B 细胞”、“活化 CD4T 细胞”、“嗜酸性粒细胞”、“中性粒细胞”和“17 型辅助性 T 细胞”表现出高免疫浸润，而 FOSB、KLF6 和 MYBL2 与 17 型辅助性 T 细胞呈显著负相关。
结论
我们的研究结果表明载脂蛋白 D（APOD）的表达水平与 OA 相关。此外，构建了转录调控-免疫网络，可能有助于 OA 的治疗。
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