椎间盘退变是引起腰痛的最主要原因。基质金属蛋白酶（Matrix metalloproteinases，MMPs）是降解椎间盘细胞外基质，引起椎间盘退变的最重要的蛋白酶。IL-1在椎间盘退变过程中扮演重要角色，其表达上调会导致椎间盘内MMPs的生成增加。前期研究表明Wnt/β-catenin信号通路通过调节MMPs在椎间盘退变进程中起关键作用。以上结果强烈提示IL-1→Wnt/β-catenin→MMPs这一信号转导系统在椎间盘退变时发挥重要作用。我们研究发现补肾活血方能有效改善椎间盘退变的病理变化。但其具体的作用靶点需要深入探究。因此，我们假设补肾活血方通过调控椎间盘细胞内IL-1→Wnt/β-catenin→MMPs信号转导系统起到防治椎间盘退变的作用。本项目借助转基因和基因敲除模式动物，对该假设进行研究，以期初步阐明补肾活血方的作用靶点，为进一步探索补肾活血方起效的物质基础奠定基础。

Low back pain is a serious clinical problem and often related to intervertebral disc (IVD) degeneration. The mechanism responsible for this disease remains unknown. Interleukin-1 (IL-1) is a cytokine which plays an important role in inflammation and disc degeneration. β-catenin is a central molecule of canonical Wnt signaling and plays a key role in disc function. In preliminary studies, we found that IL-1 up-regulated chemokines, such as Ccl2, Ccl3 and Ccl5 in human disc cells. IL-1 induces β-catenin nuclear translocation in chondrocytes. β-catenin protein levels are also significantly up-regulated in disc tissues from patients with disc degeneration. To determine the function of β-catenin in disc cells and disc degeneration, we have generated and analyzed β-catenin conditional activation mice (β-catenin(ex3)Col2ER). These mice display severe defects in disc tissues, including extensive osteophyte formation, severe disorganized annulus fibrosus (AF) and nucleus pulposus (NP) tissues and up-regulation of MMPs in disc cells. These findings laid a strong foundation for further investigation of the role of β-catenin signaling in IL-1-induced chemokine regulation and disc degeneration. Based on preliminary findings we hypothesize that IL-1 causes disc degeneration partially through activation of β-catenin→chemokines→MMPs signaling pathway in disc cells. To test this hypothesis, we propose two specific aims. In Aim 1, we will determine the role β-catenin in IL-1-induced chemokines and MMPs regulation. In Aim 2, we will determine if deletion of Ccr1 will reverse defects observed in disc tissues of β-catenin(ex3)Agc1ER mice. Our proposed studies will provide novel insights into mechanisms of IL-1 and β-catenin signaling in disc cells and in the development of disc degeneration.