Xu Yili, Xie Zuozhi, Gu Shubo, Zhao Xiang, Zhao Di, Wu Zhengzheng, Wang Jinfeng, Xu Tao, Xu Ruxue, Feng Zhenhua, Qiu Yong, Zhu Zezhang, Yu Yang, Shi Bo, Jiang Jun
Division of Spine Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital, Clinical College of Nanjing University of Chinese Medicine, Nanjing, 210008, China.
Division of Spine Surgery, Department of Orthopedic Surgery, Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing, 210008, China.
J Transl Med. 2025 Aug 6;23(1):867. doi: 10.1186/s12967-025-06798-4.
Intervertebral disc degeneration (IDD) is a primary cause of low back pain and, in severe cases, can lead to disability. Current treatments for low back pain remain limited in efficacy, underscoring the need for a deeper understanding of the molecular mechanisms driving IDD. The degeneration process is primarily driven by an imbalance in the extracellular matrix, largely due to the senescence of nucleus pulposus cells (NPCs).
Through single-cell sequencing of degenerated nucleus pulposus tissue from five intervertebral discs, we identified five distinct NPC subtypes. Notably, fibrosis-associated NPCs (Fibro-NPC) were predominantly observed at the terminal stage of cell differentiation, identifying Fibro-NPC as a pathogenic subtype in IDD. To further explore intercellular interactions, we used the CellChat algorithm to construct a cell communication network encompassing the diverse cell types in the nucleus pulposus. Mass spectrometry analysis of normal and degenerated tissue subsequently identified seven core proteins associated with IDD. Among these, WGCNA and machine learning highlighted SFRP4 as a central pathogenic protein, highly expressed in Fibro-NPC.
Advanced differentiation of nucleus pulposus cells, particularly the Fibro-NPC subtype, is associated with the secretion of SFRP4, which accelerates cellular senescence. This senescence contributes to fibrosis within the nucleus pulposus, along with angiogenesis and inflammatory infiltration in the nucleus pulposus microenvironment. Collectively, these processes drive intervertebral disc degeneration.
Our findings position SFRP4 as a biomarker for IDD, presenting a novel target for its diagnosis and treatment.
椎间盘退变（IDD）是腰背痛的主要原因，严重时可导致残疾。目前针对腰背痛的治疗效果仍然有限，这凸显了深入了解驱动IDD的分子机制的必要性。退变过程主要由细胞外基质失衡驱动，这在很大程度上归因于髓核细胞（NPC）的衰老。
通过对五个椎间盘退变髓核组织进行单细胞测序，我们鉴定出五种不同的NPC亚型。值得注意的是，纤维化相关NPC（Fibro-NPC）主要在细胞分化的终末期被观察到，这表明Fibro-NPC是IDD中的一种致病亚型。为了进一步探索细胞间相互作用，我们使用CellChat算法构建了一个包含髓核中多种细胞类型的细胞通讯网络。随后对正常组织和退变组织进行质谱分析，鉴定出七种与IDD相关的核心蛋白。其中，加权基因共表达网络分析（WGCNA）和机器学习突出显示分泌型卷曲相关蛋白4（SFRP4）是一种核心致病蛋白，在Fibro-NPC中高度表达。
髓核细胞的晚期分化，特别是Fibro-NPC亚型，与SFRP4的分泌有关，SFRP4会加速细胞衰老。这种衰老导致髓核内纤维化，以及髓核微环境中的血管生成和炎症浸润。这些过程共同推动椎间盘退变。
我们的研究结果将SFRP4定位为IDD的生物标志物，为其诊断和治疗提供了一个新的靶点。
