Huang Pan, He Yi, Zhi Na, Yi Wenqi, Guo Caixia, Jiang ZeFei, Zhang Hong
Acupunctrue and Tuina School, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province, 610000, China.
Eur Spine J. 2025 Jun 9. doi: 10.1007/s00586-025-09005-6.
Growing evidence indicates that inflammatory cytokines may influence intervertebral disc degeneration both upstream and downstream. To further explore the upstream and downstream direct causality of inflammatory cytokines in intervertebral disc degeneration, we performed a bidirectional, two-sample Mendelian randomization (MR) study.
Five MR analysis techniques were used to explore the causal relationship, with a sensitivity analysis validating the results. We examined 91 inflammatory cytokines to assess their impact on intervertebral disc degeneration and identify upstream modulators. Three key regulators were identified: cystatin D(OR, 0.88; CI [0.78-1.00]; P = 0.04), IL-15 receptor subunit alpha (OR, 1.17; CI [1.02-1.34]; P = 0.02), and TNF-related apoptosis-inducing ligand (OR, 0.85; CI [0.75-0.98]; P = 0.02). Additionally, we examined the effects of disc degeneration on inflammatory cytokines to identify downstream effectors influencing disc degeneration. We identified four downstream effectors associated with disc degeneration: IL-13(OR 1.05, CI 1.01-1.10, P = 0.01), IL-2 (OR 0.95, CI 0.91-0.99, P = 0.02), IL-20 receptor subunit alpha (OR, 1.05; CI [1.01-1.09]; P = 0.03), and Thymic stromal lymphopoietin(OR, 1.05; CI [1.00-1.10]; P = 0.02).
This research identified a causal link between inflammatory cytokines and intervertebral disc degeneration, highlighting Cystatin D, IL-15 receptor subunit alpha, and TNF-related apoptosis-inducing ligand as key regulators, with IL-15 receptor subunit alpha possibly being the primary factor. Our hypothesis proposes that after disc degeneration, increased IL-13 and decreased IL-2 levels might slow disc degeneration and provide a protective response. Conversely, higher levels of IL-20 receptor subunit alpha and thymic stromal lymphopoietin could exacerbate inflammation and accelerate disc degeneration.
越来越多的证据表明，炎性细胞因子可能在椎间盘退变的上下游均产生影响。为了进一步探究炎性细胞因子在椎间盘退变中的上下游直接因果关系，我们进行了一项双向双样本孟德尔随机化（MR）研究。
使用五种MR分析技术来探究因果关系，并通过敏感性分析验证结果。我们检测了91种炎性细胞因子，以评估它们对椎间盘退变的影响并确定上游调节因子。确定了三个关键调节因子：胱抑素D（比值比[OR]，0.88；可信区间[CI][0.78 - 1.00]；P = 0.04）、白细胞介素15受体α亚基（OR，1.17；CI[1.02 - 1.34]；P = 0.02）和肿瘤坏死因子相关凋亡诱导配体（OR，0.85；CI[0.75 - 0.98]；P = 0.02）。此外，我们检测了椎间盘退变对炎性细胞因子的影响，以确定影响椎间盘退变的下游效应因子。我们确定了四个与椎间盘退变相关的下游效应因子：白细胞介素13（OR 1.05，CI 1.01 - 1.10，P = 0.01）、白细胞介素2（OR 0.95，CI 0.91 - 0.99，P = 0.02）、白细胞介素20受体α亚基（OR，1.05；CI[1.01 - 1.09]；P = 0.03）和胸腺基质淋巴细胞生成素（OR，1.05；CI[1.00 - 1.10]；P = 0.02）。
本研究确定了炎性细胞因子与椎间盘退变之间的因果联系，突出了胱抑素D、白细胞介素15受体α亚基和肿瘤坏死因子相关凋亡诱导配体作为关键调节因子，其中白细胞介素15受体α亚基可能是主要因素。我们的假设提出，在椎间盘退变后，白细胞介素13水平升高和白细胞介素2水平降低可能会减缓椎间盘退变并提供一种保护反应。相反，白细胞介素20受体α亚基和胸腺基质淋巴细胞生成素水平升高可能会加剧炎症并加速椎间盘退变。
