椎间盘退变过程中髓核细胞代谢失衡，功能性细胞外基质降解加快，ADAMTS-4、5具有促进胞外基质降解的重要作用。因此，深入研究ADAMTS-4、5的调控机制尤为重要。我们前期发现椎间盘退变患者髓核组织HtrA1的表达与椎间盘退变程度相关，且HtrA1能上调髓核细胞ADAMTS-4、5的表达。文献报道ADAMTS-4、5的表达可受NF-κB及MAPK通路的调控。根据前期研究结合文献报道，我们认为：HtrA1可通过NF-κB或MAPK通路促进ADAMTS-4、5的表达，从而降解细胞外基质，促进椎间盘退变。我们拟：①通过qPCR、Western-blot、免疫荧光等方法证实HtrA1对ADAMTS-4、5表达的影响；②通过NF-κB或MAPK通路的激活/抑制探讨HtrA1促进ADAMTS-4、5表达的信号转导机制；③体内实验验证HtrA1-NF-κB/MAPK信号轴阻断剂对椎间盘退变的防治作用。

Metabolic imbalance of nucleus pulposus cells, which induces acceleration of degradation of functional extracelluar matrix, exists during intervertebral disc degeneration. A disintegrin and metalloproteinase with thrombospondin motifs-4 and 5 (ADAMTS-4, 5) play an important role in this process of degradation of extracellular matrix. Therefore, further research in the regulation of ADAMTS-4 and 5 is particularly important. We previously found that HtrA1 mRNA expression level in nucleus pulposus of patients with disc degeneration was associated with the grade of disc degeneration, and HtrA1 can improve the level of ADAMTS-4 and 5 expression in nucleus pulposus cells. Several other studies have shown that the expression of ADAMTS-4 and 5 may be regulated by NF-κB or MAPK pathway. So we think that the HtrA1 can upregulate the expression of ADAMTS-4 and 5 via NF-κB or MAPK pathway to degrade extracellular matrix and promote disc degeneration. In order to test the hypothesis, we intend to do the following studies: ① investigate the effect of HtrA1 on the expression of ADAMTS-4 and 5 in nucleus pulposus cells using qPCR, Western-Blot, and immunofluorescence methods; ② investigate the mechanism of effect of HtrA1 promoting expression of ADAMTS-4 and 5 through the activation/inhibition of NF-κB or MAPK pathway; ③ verify the effect of blockers of HtrA1-NF-κB/MAPK on the prevention of disc degeneration by in vivo experiments.