Department of Orthopedics, Changzhou Fourth People's Hospital, Changzhou, 213000, China.
Department of Pediatric, Changzhou Fourth People's Hospital, Changzhou, 213000, China.
BMC Musculoskelet Disord. 2024 Aug 8;25(1):634. doi: 10.1186/s12891-024-07738-x.
Although rheumatoid arthritis (RA) is a chronic systemic tissue disease often accompanied by osteoporosis (OP), the molecular mechanisms underlying this association remain unclear. This study aimed to elucidate the pathogenesis of RA and OP by identifying differentially expressed mRNAs (DEmRNAs) and long non-coding RNAs (lncRNAs) using a bioinformatics approach.
Expression profiles of individuals diagnosed with OP and RA were retrieved from the Gene Expression Omnibus database. Differential expression analysis was conducted. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes pathway (KEGG) pathway enrichment analyses were performed to gain insights into the functional categories and molecular/biochemical pathways associated with DEmRNAs. We identified the intersection of common DEmRNAs and lncRNAs and constructed a protein-protein interaction (PPI) network. Correlation analysis between the common DEmRNAs and lncRNAs facilitated the construction of a coding-non-coding network. Lastly, serum peripheral blood mononuclear cells (PBMCs) from patients with RA and OP, as well as healthy controls, were obtained for TRAP staining and qRT-PCR to validate the findings obtained from the online dataset assessments.
A total of 28 DEmRNAs and 2 DElncRNAs were identified in individuals with both RA and OP. Chromosomal distribution analysis of the consensus DEmRNAs revealed that chromosome 1 had the highest number of differential expression genes. GO and KEGG analyses indicated that these DEmRNAs were primarily associated with " platelets (PLTs) degranulation", "platelet alpha granules", "platelet activation", "tight junctions" and "leukocyte transendothelial migration", with many genes functionally related to PLTs. In the PPI network, MT-ATP6 and PTGS1 emerged as potential hub genes, with MT-ATP6 originating from mitochondrial DNA. Co-expression analysis identified two key lncRNA-mRNA pairs: RP11 - 815J21.2 with MT - ATP6 and RP11 - 815J21.2 with PTGS1. Experimental validation confirmed significant differential expression of RP11-815J21.2, MT-ATP6 and PTGS1 between the healthy controls and the RA + OP groups. Notably, knockdown of RP11-815J21.2 attenuated TNF + IL-6-induced osteoclastogenesis.
This study successfully identified shared dysregulated genes and potential therapeutic targets in individuals with RA and OP, highlighting their molecular similarities. These findings provide new insights into the pathogenesis of RA and OP and suggest potential avenues for further research and targeted therapies.
类风湿关节炎（RA）是一种常伴有骨质疏松症（OP）的慢性系统性组织疾病，但两者相关的分子机制尚不清楚。本研究旨在通过生物信息学方法，鉴定差异表达的信使 RNA（DEmRNAs）和长非编码 RNA（lncRNAs），阐明 RA 和 OP 的发病机制。
从基因表达综合数据库中检索诊断为 OP 和 RA 的个体的表达谱。进行差异表达分析。进行基因本体论（GO）和京都基因与基因组百科全书（KEGG）通路富集分析，以深入了解与 DEmRNAs 相关的功能类别和分子/生化途径。我们鉴定了常见 DEmRNAs 和 lncRNAs 的交集，并构建了一个蛋白质-蛋白质相互作用（PPI）网络。常见 DEmRNAs 和 lncRNAs 之间的相关性分析有助于构建编码-非编码网络。最后，从 RA 和 OP 患者以及健康对照者中获得外周血单个核细胞（PBMCs）进行 TRAP 染色和 qRT-PCR，以验证从在线数据集评估中获得的发现。
在同时患有 RA 和 OP 的个体中，共鉴定出 28 个 DEmRNAs 和 2 个 DElncRNAs。共识 DEmRNAs 的染色体分布分析表明，染色体 1 具有最多数量的差异表达基因。GO 和 KEGG 分析表明，这些 DEmRNAs 主要与“血小板（PLTs）脱颗粒”、“血小板α颗粒”、“血小板活化”、“紧密连接”和“白细胞穿过内皮迁移”相关，许多基因与 PLTs 功能相关。在 PPI 网络中，MT-ATP6 和 PTGS1 作为潜在的枢纽基因出现，其中 MT-ATP6 来自线粒体 DNA。共表达分析确定了两个关键的 lncRNA-mRNA 对：RP11-815J21.2 与 MT-ATP6 和 RP11-815J21.2 与 PTGS1。实验验证证实了 RP11-815J21.2、MT-ATP6 和 PTGS1 在健康对照组和 RA+OP 组之间的显著差异表达。值得注意的是，RP11-815J21.2 的敲低可减弱 TNF+IL-6 诱导的破骨细胞生成。
本研究成功鉴定了 RA 和 OP 个体中共同失调的基因和潜在的治疗靶点，突出了它们的分子相似性。这些发现为 RA 和 OP 的发病机制提供了新的见解，并为进一步的研究和靶向治疗提供了潜在的途径。
