Jiang Nizhou, Wang Quanxiang, Hu Zhenxin, Tian Xiliang
Department of Spine Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, People's Republic of China.
Department of Otolaryngology-Head and Neck Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, People's Republic of China.
J Inflamm Res. 2025 Jan 29;18:1353-1375. doi: 10.2147/JIR.S505296. eCollection 2025.
Intervertebral disc degeneration (IVDD) is a common chronic degenerative disease with a complex etiology involving genetic and environmental factors. However, the genetic pathogenesis and key driving factors of IVDD remain largely unknown.
In this study, we combined MR with transcriptomic sequencing to identify key pathogenic genes implicated in IVDD. Further exploration using single-cell transcriptomics elucidated the specific cell types and pathways through which these genes modulate IVDD. Mediational MR analysis provided insights into the intermediary roles of 91 inflammatory factors and serum metabolites in the genetic causation pathway of IVDD. Finally, we validated these findings through in vitro experiments, confirming the regulatory roles of these critical genes in the progression of IVDD.
Transcriptomic and MR analyses identified six candidate pathogenic genes (AEN, CLEC11A, HMGN1, LRRC25, TAF7, and TREM1) significantly associated with IVDD. Subsequent single-cell analysis suggested that CLEC11A, TREM1, and HMGN1 may play pivotal roles in IVDD progression by modulating chondrocyte function and inflammatory responses. Mediation MR analysis further indicated that CLEC11A might significantly elevate IVDD risk by upregulating the inflammatory mediator ARTN and the uncharacterized serum metabolites X-12731 and X-18901 (ARTN: OR=1.078, 95% CI: 1.004-1.158, P=0.038; X-12731: OR=0.906, 95% CI: 0.852-0.960, P=0.043; X-18901: OR=1.090, 95% CI: 1.007-1.179, P=0.034). In vitro experiments demonstrated that overexpression of CLEC11A in nucleus pulposus cells significantly enhanced mRNA and protein expression of IVDD-related inflammatory markers; conversely, silencing CLEC11A markedly reduced these expressions. Similarly, overexpression of ARTN significantly increased, while knockdown decreased, the expression of these inflammatory markers in nucleus pulposus cells.
Our integrative multi-omics analysis indicates that CLEC11A exacerbates IVDD by upregulating ARTN and inducing metabolic dysregulation, thereby amplifying the inflammatory pathways that drive disease progression.
椎间盘退变（IVDD）是一种常见的慢性退行性疾病，其病因复杂，涉及遗传和环境因素。然而，IVDD的遗传发病机制和关键驱动因素仍 largely未知。
在本研究中，我们将磁共振成像（MR）与转录组测序相结合，以鉴定与IVDD相关的关键致病基因。使用单细胞转录组学进行的进一步探索阐明了这些基因调节IVDD的特定细胞类型和途径。中介MR分析深入了解了91种炎症因子和血清代谢物在IVDD遗传因果途径中的中介作用。最后，我们通过体外实验验证了这些发现，证实了这些关键基因在IVDD进展中的调节作用。
转录组学和MR分析确定了六个与IVDD显著相关的候选致病基因（AEN、CLEC11A、HMGN1、LRRC25、TAF7和TREM1）。随后的单细胞分析表明，CLEC11A、TREM1和HMGN1可能通过调节软骨细胞功能和炎症反应在IVDD进展中起关键作用。中介MR分析进一步表明，CLEC11A可能通过上调炎症介质ARTN以及未鉴定的血清代谢物X-12731和X-18901来显著增加IVDD风险（ARTN：OR=1.078，95%CI：1.004-1.158，P=0.038；X-12731：OR=0.906，95%CI：0.852-0.960，P=0.043；X-18901：OR=1.090，95%CI：1.007-1.179，P=0.034）。体外实验表明髓核细胞中CLEC11A的过表达显著增强了IVDD相关炎症标志物的mRNA和蛋白质表达；相反，沉默CLEC11A显著降低了这些表达。同样，ARTN的过表达显著增加，而敲低则降低了髓核细胞中这些炎症标志物的表达。
我们的综合多组学分析表明，CLEC11A通过上调ARTN和诱导代谢失调来加重IVDD，从而放大驱动疾病进展的炎症途径。
