Li Fangyu, Wang Ying, Cao Jie, Chen Qi, Gao Yuanyuan, Li Rui, Yuan Li
Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Front Pharmacol. 2024 Jun 20;15:1388205. doi: 10.3389/fphar.2024.1388205. eCollection 2024.
The relationship between type 2 diabetes mellitus (T2DM) and osteoporosis (OP) has been widely recognized in recent years, but the mechanism of interaction remains unknown. The aim of this study was to investigate the genetic features and signaling pathways that are shared between T2DM and OP.
We analyzed the GSE76894 and GSE76895 datasets for T2DM and GSE56815 and GSE7429 for OP from the Gene Expression Omnibus (GEO) database to identify shared genes in T2DM and OP, and we constructed coexpression networks based on weighted gene coexpression network analysis (WGCNA). Shared genes were then further analyzed for functional pathway enrichment. We selected the best common biomarkers using the least absolute shrinkage and selection operator (LASSO) algorithm and validated the common biomarkers, followed by RT-PCR, immunofluorescence, Western blotting, and enzyme-linked immunosorbent assay (ELISA) to validate the expression of these hub genes in T2DM and OP mouse models and patients.
We found 8,506 and 2,030 DEGs in T2DM and OP, respectively. Four modules were identified as significant for T2DM and OP using WGCNA. A total of 19 genes overlapped with the strongest positive and negative modules of T2DM and OP. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed these genes may be involved in pantothenate and CoA biosynthesis and the glycosaminoglycan biosynthesis-chondroitin sulfate/dermatan sulfate and renin-angiotensin system signaling pathway. The LASSO algorithm calculates the six optimal common biomarkers. RT-PCR results show that , and were upregulated in T2DM and OP. Immunofluorescence and Western blot show that is upregulated in the pancreas and bones of T2DM model mice and osteoporosis model mice. Similarly, the level of in the sera of patients with T2DM, OP, and T2DM and OP was higher than that in the healthy group.
Based on the WGCNA and LASSO algorithms, we identified genes and pathways that were shared between T2DM and OP. Both pantothenate and CoA biosynthesis and the glycosaminoglycan biosynthesis-chondroitin sulfate/dermatan sulfate and renin-angiotensin systems may be associated with the pathogenesis of T2DM and OP. Moreover, may be a potential diagnostic marker for patients with T2DM complicated by OP. This study provides a new perspective for the systematic study of possible mechanisms of combined OP and T2DM.
近年来，2型糖尿病（T2DM）与骨质疏松症（OP）之间的关系已得到广泛认可，但两者相互作用的机制仍不清楚。本研究旨在探讨T2DM和OP之间共享的遗传特征和信号通路。
我们分析了来自基因表达综合数据库（GEO）的T2DM的GSE76894和GSE76895数据集以及OP的GSE56815和GSE7429数据集，以确定T2DM和OP中的共享基因，并基于加权基因共表达网络分析（WGCNA）构建共表达网络。然后对共享基因进行功能通路富集分析。我们使用最小绝对收缩和选择算子（LASSO）算法选择最佳的共同生物标志物，并对共同生物标志物进行验证，随后通过逆转录聚合酶链反应（RT-PCR）、免疫荧光、蛋白质免疫印迹和酶联免疫吸附测定（ELISA）来验证这些核心基因在T2DM和OP小鼠模型及患者中的表达。
我们在T2DM和OP中分别发现了8506个和2030个差异表达基因（DEG）。使用WGCNA鉴定出四个对T2DM和OP具有显著意义的模块。共有19个基因与T2DM和OP的最强正、负模块重叠。京都基因与基因组百科全书（KEGG）分析表明，这些基因可能参与泛酸和辅酶A生物合成以及糖胺聚糖生物合成 - 硫酸软骨素/硫酸皮肤素和肾素 - 血管紧张素系统信号通路。LASSO算法计算出六个最佳的共同生物标志物。RT-PCR结果显示，[具体基因名称1]、[具体基因名称2]和[具体基因名称叁]在T2DM和OP中上调。免疫荧光和蛋白质免疫印迹显示，[具体基因名称肆]在T2DM模型小鼠和骨质疏松症模型小鼠的胰腺和骨骼中上调。同样，T2DM患者、OP患者以及T2DM合并OP患者血清中的[具体基因名称肆]水平高于健康组。
基于WGCNA和LASSO算法，我们鉴定出了T2DM和OP之间共享的基因和通路。泛酸和辅酶A生物合成以及糖胺聚糖生物合成 - 硫酸软骨素/硫酸皮肤素和肾素 - 血管紧张素系统可能都与T2DM和OP的发病机制有关。此外，[具体基因名称肆]可能是T2DM合并OP患者的潜在诊断标志物。本研究为系统研究OP合并T2DM的可能机制提供了新的视角。
