HMGB-1通过MAPK/NF-κB信号通路调控椎间盘细胞功能促进椎间盘退变的机制研究

炎性反应与椎间盘退变的发生密切相关，但退变椎间盘内炎性反应发生的始动因素仍不明确。研究发现HMGB-1在多种炎症相关性疾病中与RAGE、TLR受体结合后可激活MAPK/NF-κB信号通路，从而发挥很强的促炎作用，然而HMGB-1对于椎间盘细胞的生物学作用尚不清楚。我们的前期研究发现HMGB-1在退变椎间盘组织中可以表达，进一步实验表明HMGB-1可以促进髓核细胞中炎性介质与基质降解酶的表达。根据既往研究及我们前期研究结果，我们提出科学假设：HMGB-1可以通过与RAGE、TLR受体结合，激活MAPK/NF-κB信号通路，促进髓核细胞和纤维环细胞中炎性介质、基质降解酶和趋化因子的分泌，从而导致椎间盘退变和腰痛的发生。本课题拟通过细胞模型与动物模型验证以上科学假设，为将HMGB-1作为椎间盘退变生物治疗的新靶点提供理论依据。

Inflammatory response is closely related to the occurrence of intervertebral disc degeneration, but the initiating factors of inflammatory response in degenerative intervertebral disc are still unclear. HMGB-1 has been demonstrated to bind to RAGE and TLR receptors to activate MAPK/NF-κB signaling pathways in several inflammatory diseases, with promoting strong inflammation. However, the biological role of HMGB-1 playing in intervertebral disc cells is unclear. Our preliminary studies have suggested that HMGB-1may be expressed in degenerative intervertebral disc, and HMGB-1 may stimulate the expression of inflammatory mediators and matrix degrading enzymes in nucleus pulposus cell. Accordingly, we propose the following hypothesis: HMGB-1 can stimulate the expression of inflammatory mediators, matrix degrading enzymes and chemokines through binding to RAGE and TLR receptors to activate MAPK/NF-κB signaling pathways, finally causing disc degeneration and low back pain. The current project will verify the above hypothesis by applying cell and animal model, and provide new targets for biological therapy of disc degeneration.