Department of Joints, Tianjin Hospital, Tianjin University, Tianjin, China.
Clinical College of Orthopedics, Tianjin Medical University, Tianjin, China.
J Biol Regul Homeost Agents. 2021 Aug 27;35(4). doi: 10.23812/21-246-A. Epub 2021 Jul 23.
Disuse osteoporosis (DOP) is one of the major consequences of long space flights. DOP also occurs in patients with spinal cord injuries and prolonged bedridden states that can have a severe impact on human health. Bone marrow mesenchymal stem cells (BMSCs) are multipotent stromal cells that play an important role in bone homeostasis. Long non-coding RNAs (lncRNAs) are involved in regulating osteogenic differentiation of BMSCs, and their abnormal expression might lead to the formation of orthopedic diseases. However, the specific mechanism of DOP has not yet been elucidated. All sequencing data were obtained from Gene Expression Omnibus (GEO) datasets. The limma package of R was applied to identify DEmRNAs and DElncRNAs. Pearson correlation coefficients (PCC) between DElncRNADEmRNA expression levels were calculated. Functional annotation was performed for DEmRNAs coexpressed with DElncRNAs. In addition, the Cytohubba plug-in in Cytoscape was applied to determine the top 10 hub genes. Finally, connectivity map (CMap) analysis was used to identify potential therapeutic drugs for DOP. The gene expression data, GSE100930 and GSE17696, were retrieved from the GEO database. A total of 2,212 differentially expressed mRNAs (DEmRNAs) and 22 differentially expressed lncRNAs (DElncRNAs) were obtained. Gene ontology (GO) functional terms, Kyoto Encyclopedia of Genes, and Genomes (KEGG) pathway enrichment analysis reveal 30 significant GO terms and 13 significant pathways. A coding-non-coding gene co-expression (CNC) network was constructed to study the potential role of hub-DElncRNAs and their co-expressed DEmRNAs in DOP. The lncRNAs, GSNAS1, SNHG12, and EPB41LA4A-AS1, were significant in the CNC network and potential regulators of DOP development. Three bioactive compounds (scoulerine, kinetin riboside, dexanabinol) with potential therapeutic significance for DOP were obtained through the Connectivity Map (CMAP) analysis. Our study revealed a new mechanism for a lineage shift of bone marrow mesenchymal stem cells under microgravity, and linked the function of protein-coding mRNAs with ncRNAs, which may contribute to the development of new therapies for DOP.
废用性骨质疏松症（DOP）是长期太空飞行的主要后果之一。DOP 也发生在脊髓损伤和长期卧床不起的患者中，这会对人类健康造成严重影响。骨髓间充质干细胞（BMSCs）是多能基质细胞，在骨稳态中发挥重要作用。长链非编码 RNA（lncRNA）参与调节 BMSCs 的成骨分化，其异常表达可能导致骨科疾病的形成。然而，DOP 的具体机制尚未阐明。所有测序数据均来自基因表达综合数据库（GEO）数据集。R 中的 limma 包用于识别 DEmRNAs 和 DElncRNAs。计算 DElncRNA-DEmRNA 表达水平之间的 Pearson 相关系数（PCC）。对与 DElncRNA 共表达的 DEmRNAs 进行功能注释。此外，在 Cytoscape 中应用 Cytohubba 插件确定前 10 个枢纽基因。最后，通过连接图谱（CMap）分析确定 DOP 的潜在治疗药物。从 GEO 数据库中检索到基因表达数据 GSE100930 和 GSE17696。共获得 2212 个差异表达的 mRNA（DEmRNAs）和 22 个差异表达的 lncRNA（DElncRNAs）。GO 功能术语、京都基因与基因组百科全书（KEGG）通路富集分析揭示了 30 个显著的 GO 术语和 13 个显著的通路。构建编码非编码基因共表达（CNC）网络，以研究枢纽 DElncRNA 及其共表达的 DEmRNA 在 DOP 中的潜在作用。lncRNA GSNAS1、SNHG12 和 EPB41LA4A-AS1 在 CNC 网络中显著，是 DOP 发展的潜在调节剂。通过连接图谱（CMAP）分析获得了 3 种具有潜在治疗意义的生物活性化合物（千里光碱、激动素核苷、屈大麻酚）。本研究揭示了微重力下骨髓间充质干细胞谱系转移的新机制，并将蛋白质编码 mRNAs 的功能与 ncRNAs 联系起来，这可能有助于开发 DOP 的新疗法。
