中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2023, Vol. 18 ›› Issue (3): 634-642.doi: 10.4103/1673-5374.350210

• 原著:脊髓损伤修复保护与再生 • 上一篇    下一篇

富含半胱氨酸的酸性分泌蛋白缺失小鼠存在与椎间盘退变相关的慢性脊髓压迫

  

  • 出版日期:2023-03-15 发布日期:2022-08-28
  • 基金资助:

    中国国家自然科学基金项目（82074454，82174409，81930116，81873317），国家重点研发计划项目（2018YFC1704300），上海市自然科学基金项目（20ZR1459000）

Chronic spinal cord compression associated with intervertebral disc degeneration in SPARC-null mice

Zhuo-Yao Li1, 2, #, Ai-Fang Zhou1, 2, #, Gan Li1, 2, Long-Yun Zhou3, Pei-Min Pu1, 2, Ke Zhu1, 2, Zhong Zheng1, 2, Yong-Jun Wang1, 2, Qian-Qian Liang1, 2, *, Min Yao1, 2, *, Xue-Jun Cui1, 2, *   

  1. 1Spine Disease Institute, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China; 2Key Laboratory of Theory and Therapy of Muscles and Bones, Ministry of Education, Shanghai University of Traditional Chinese Medicine, Shanghai, China; 3Rehabilitation Medicine Center, Jiangsu Province Hospital, Nanjing, Jiangsu Province, China
  • Online:2023-03-15 Published:2022-08-28
  • Contact: Xue-Jun Cui, PhD, 13917715524@139.com; Min Yao, PhD, yaomin19871223@126.com; Qian-Qian Liang, PhD, liangqianqiantcm@126.com.
  • Supported by:
    This work was supported by the National Natural Science Foundation of China, Nos. 82074454 (to XJC), 82174409 (to MY), 81930116 (to YJW), 81873317 (to XJC), the National Key R&D Program of China, No. 2018YFC1704300 (to YJW), the Natural Science Foundation of Shanghai, No. 20ZR1459000 (to MY).

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摘要：

由于啮齿类动物很少发生自发性椎间盘突出，因此建立一种慢性脊髓压迫动物模型对于探索这种疾病的机制和治疗至关重要。由于富含半胱氨酸的酸性分泌蛋白缺失可导致小鼠发生自发性椎间盘退变，且其表现类似于临床椎间盘退变。为探索富含半胱氨酸的酸性分泌蛋白基因敲除小鼠是否可作为慢性脊髓压迫动物模型，实验进行了转杆测试、疼痛阈值测试、步态分析和BMS评分，结果显示，富含半胱氨酸的酸性分泌蛋白基因敲除小鼠运动功能有所下降，同时核磁共振检查也可见明显椎间盘突出和脊髓压迫，尤其是腰部节段。进一步免疫荧光染色及蛋白印迹结果显示，受压部位存在神经元和少突胶质细胞凋亡，激活的M1和M2型小胶质/巨噬细胞以及A1和A2型星形胶质细胞，且还存在NLRP3炎性小体活化，而脑源性神经营养因子/TrkB信号通路受抑制的现象。上述所有表现均为慢性脊髓压迫的特征性病理改变。因此，作者认为，富含半胱氨酸的酸性分泌蛋白缺失小鼠可作为研究椎间盘突出引起的慢性脊髓压迫的一种稳定且理想的动物模型。

https://orcid.org/0000-0002-9006-4547 (Xue-Jun Cui); https://orcid.org/0000-0002-0410-7900 (Min Yao); https://orcid.org/0000-0003-2286-8647 (Zhuo-Yao Li)

关键词:

慢性脊髓压迫, 富含半胱氨酸的酸性分泌蛋白, 椎间盘退变, 椎间盘突出, 神经炎症, 神经元, 小胶质细胞, 巨噬细胞, 星形胶质细胞, 细胞凋亡, NLRP3炎性小体

Abstract: Chronic spinal cord compression (CSCC) is induced by disc herniation and other reasons, leading to movement and sensation dysfunction, with a serious impact on quality of life. Spontaneous disc herniation rarely occurs in rodents, and therefore establishing a chronic spinal cord compression (CSCC) animal model is of crucial importance to explore the pathogenesis and treatment of CSCC. The absence of secreted protein, acidic, and rich in cysteine (SPARC) leads to spontaneous intervertebral disc degeneration in mice, which resembles human disc degeneration. In this study, we evaluated whether SPARC-null mice may serve as an animal model for CSCC. We performed rod rotation test, pain threshold test, gait analysis, and Basso Mouse Scale score. Our results showed that the motor function of SPARC-null mice was weakened, and magnetic resonance images revealed compression at different spinal cord levels, particularly in the lumbar segments. Immunofluorescence staining and western blot assay showed that the absence of SPARC induced apoptosis of neurons and oligodendrocytes, activation of microglia/macrophages with M1/M2 phenotype and astrocytes with A1/A2 phenotype; it also activated the expression of the NOD-like receptor protein 3 inflammasome and inhibited brain-derived neurotrophic factor/tyrosine kinase B signaling pathway. Notably, these findings are characteristics of CSCC. Therefore, we propose that SPARC-null mice may be an animal model for studying CSCC caused by disc herniation.

Key words: apoptosis, astrocytes, chronic spinal cord compression, disc degeneration, disc herniation, macrophages, microglia, neuroinflammation, neurons, NOD-like receptor protein 3 inflammasomes, secreted protein, acidic, and rich in cysteine