关节突关节源性下腰痛发病过程中GalT-I和SSeCKS调控TNF-α自分泌的机制

Inflammatory cytokines mediated inflammatory cascade response plays an important role in the pathogenesis of low back pain from facet joints. Recent studies have found that inflammatory cytokines can penetrate to the surrounding of dorsal root ganglia (DRG) from lumbar facet joints and induce inflammatory response of DRG in the pathogenesis of low back pain from facet joints. Tumor necrosis factor-α (TNF-α) plays a core role in nerve inflammatory response process and can induce neuropathic pain. β-1,4-galactosyltransferase-I (GalT-I) and src-suppressed C kinase substrate (SSeCKS) can induce TNF-α autocrine. Therefore, it is very necessary to study the mechanisms of GalT-I and SSeCKS regulating TNF-α autocrine in the pathogenesis of low back pain from facet joints. First of all, we shall analyze expression changes of GalT-I, SSeCKS and TNF-α and cross-correlation among them by constructing the models of rat lumbar facet arthritis and inflammation activation of schwann cells. Then, we shall focuse on the molecular feedback mechanisms and signaling pathways that regulate TNF-α autocrine by directly intervention aimed at GalT-I and SSeCKS expression with vectors of over-expression, interference and phosphorylation and inhibitory enzyme. These findings will clarify the pathological significance of these molecular mechanisms that induced nerve root pain in low back pain from facet joints, and also provide theoretical basis to reveal the important role of the inflammatory mechanism doctrine in the pathogenesis of low back pain from facet joints and design targeted therapy sites for low back pain from facet joints for further study.

炎症因子介导的炎症级联反应在关节突关节源性下腰痛中发挥重要作用。近年研究发现，炎症因子可以从腰椎关节突关节渗透到背根神经节周围，诱发背根神经节炎症反应，而TNF-α在神经炎症反应中起核心作用，可以诱发神经性疼痛，且SSeCKS和GalT-I可以诱导TNF-α自分泌，故研究关节突关节源性下腰痛发病过程中GalT-I和SSeCKS调控TNF-α自分泌机制尤为关键。本课题首先通过构建大鼠腰椎关节突关节炎和施旺细胞炎症激活模型，分析GalT-I、SSeCKS和TNF-α的时空表达变化及相互关系；接着通过构建过表达和干扰及磷酸化载体与酶抑制剂，干预GalT-I和SSeCKS表达，重点探讨它们调控TNF-α自分泌的分子反馈机制和信号途径。阐明这种分子机制致关节突关节源性下腰痛中神经根性疼痛的病理意义，为进一步揭示炎症机制学说在关节突关节源性下腰痛发病机制中的作用和设计合理的靶向治疗位点提供理论依据。

炎症因子介导的炎症级联反应在关节突关节源性下腰痛中发挥重要作用。近年研究发现，炎症因子可以从腰椎关节突关节渗透到背根神经节周围，诱发背根神经节炎症反应，而TNF-α在神经炎症反应中起核心作用，可以诱发神经性疼痛，且SSeCKS和GalT-Ⅰ可以诱导TNF-α自分泌，故研究关节突关节源性下腰痛发病过程中GalT-Ⅰ和SSeCKS调控TNF-α自分泌机制尤为关键。课题组在项目进行过程中发现：（1）IL-1β和MMP-1等炎症因子参与了腰椎关节突关节炎（LFA）软骨和滑膜组织的炎症反应过程，且免疫荧光和细胞实验发现IL-1β通过过表达MMP-1促进关节软骨的退变；（2）LFA患者关节突关节滑膜组织中TNF-α、GalT-Ⅰ和SSeCKS表达增加，且其与LFA患者下腰痛的症状和疾病严重程度密切相关；（3）大鼠LFA和施旺细胞炎症激活模型中，TNF-α、GalT-Ⅰ和SSeCKS表达增加，且过表达及干扰等干预方法验证了GalT-Ⅰ和SSeCKS在关节突关节源性下腰痛发病过程中正向调控了TNF-α的自分泌。研究结果阐明了这些分子机制致关节突关节源性下腰痛中神经根性疼痛的病理意义，为进一步揭示炎症机制学说在关节突关节源性下腰痛发病机制中的作用和设计合理的潜在靶向治疗位点提供理论依据。