Department of Orthopaedics, Emory University, Atlanta, GA 30322, USA.
Atlanta VA Medical Center, Decatur, GA 30033, USA.
Genes (Basel). 2020 Jul 9;11(7):771. doi: 10.3390/genes11070771.
Intervertebral disc (IVD) degeneration (IDD) is a multifactorial physiological process which is often associated with lower back pain. Previous studies have identified some molecular markers associated with disc degeneration, which despite their significant contributions, have provided limited insight into the etiology of IDD. In this study, we utilized a network medicine approach to uncover potential molecular mediators of IDD. Our systematic analyses of IDD associated with 284 genes included functional annotation clustering, interaction networks, network cluster analysis and Transcription factors (TFs)-target gene network analysis. The functional enrichment and protein-protein interaction network analysis highlighted the role of inflammatory genes and cytokine/chemokine signaling in IDD. Moreover, sub-network analysis identified significant clusters possessing organized networks of 24 cytokine and chemokine genes, which may be considered as key modulators for IDD. The expression of these genes was validated in independent microarray datasets. In addition, the regulatory network analysis identified the role of multiple transcription factors, with RUNX1 being a master regulator in the pathogenesis of IDD. Our analyses highlighted the role of cytokine genes and interacting pathways in IDD and further improved our understanding of the genetic mechanisms underlying IDD.
椎间盘（IVD）退变（IDD）是一种多因素的生理过程，常与下腰痛有关。先前的研究已经确定了一些与椎间盘退变相关的分子标志物，尽管它们有重要的贡献，但对 IDD 的病因学提供的见解有限。在这项研究中，我们利用网络医学方法来揭示IDD 的潜在分子介质。我们对与 284 个基因相关的 IDD 进行了系统的分析，包括功能注释聚类、相互作用网络、网络聚类分析和转录因子（TF）-靶基因网络分析。功能富集和蛋白质-蛋白质相互作用网络分析强调了炎症基因和细胞因子/趋化因子信号在 IDD 中的作用。此外，子网络分析确定了具有 24 个细胞因子和趋化因子基因的有组织网络的显著簇，这些基因可能被认为是 IDD 的关键调节剂。这些基因的表达在独立的微阵列数据集得到了验证。此外，调控网络分析确定了多个转录因子的作用，其中 RUNX1 是 IDD 发病机制中的主要调节因子。我们的分析强调了细胞因子基因和相互作用途径在 IDD 中的作用，进一步提高了我们对 IDD 遗传机制的理解。
