椎间盘退变与腰痛有关。我们前期研究发现，椎间盘退变伴随纤维化改变。基质金属蛋白酶12（MMP12）是一个前纤维化因子与转录因子，诱导巨噬细胞和肌成纤维细胞的迁移。在其他系统中，MMP12敲除能减缓纤维化，并影响其他纤维化MMP的表达。我们对椎间盘退变候选基因的筛查表明，退变IVD中MMP12为最显著上调基因，并且MMP12与肌成纤维细胞标记蛋白存在共表达。注射间充质干细胞能降低纤维化并下调MMP12，提示MMP12与椎间盘纤维化存在重要联系。我们推测MMP12可能通过吸引巨噬细胞和促进炎症级联反应导致椎间盘纤维化。本研究将通过：1)确认MMP12与纤维化程度的联系及其细胞来源; 2）MMP12体内外敲除实验; 3）MMP12信号传递研究，来验证MMP12对椎间盘稳态的影响。这是首次关于MMP12与椎间盘退变的系统研究，为退变揭示新信号机制，鉴定新关键致病分子，为阻断退变寻求新手段。

Intervertebral disc (IVD) degeneration is a major cause of low back pain and disability, for which the etiology is not yet clear. Our recent data revealed that fibrosis had a major role in IVD degeneration. Matrix metalloproteinase 12 (MMP12) is a pro-inflammatory and pro-fibrotic factor, as well as a transcription factor. MMP12 could induce the migration of myofibroblasts and macrophages to the injured site. In other diseases, MMP12 depletion retards fibrosis, and has been reported to affect the expression of other fibrosis related MMPs, including MMP2 and MMP3, which are known to be upregulated during IVD degeneration..In a pilot study, we demonstrated that MMP12 was the most significantly upregulated gene in human IVD degeneration among other conventional degeneration indicators. Consistently, we found an increase in the number of cells positive for MMP12 expression in rat and human IVDs during degeneration. These MMP12(+) cells co-expressed α-smooth muscle actin (a-SMA) and fibroblast specific protein 1 (FSP1), which are known to also be expressed by myofibroblasts. More importantly, we found that implantation of mesenchymal stem cells (MSC) could alleviate disc degeneration in part via down-regulating MMP12 expression in degenerated NP cells..We hypothesize that MMP12 has an as yet unidentified impact on disc cell homeostasis through promoting inflammatory signaling and interaction with other MMPs, which results in IVD degeneration and fibrosis. In this proposal, we aim to fully investigate the role of MMP12 in IVD homeostasis. This will be achieved by three objectives: 1) To establish the association of MMP12 positivity with the degree of IVD fibrosis; 2) To elicidate the contribution of MMP12 to disc homeostasis through MMP12 depletion in vitro and in vivo; 3) To investigate the signaling events induced by MMP12 injection..This study will generate novel insights on how MMP12 is involved in the pathogenesis of IVD degeneration. Scientifically, revealing the role of MMP12 in IVD degeneration will help us to unravel the biological events that occur during IVD degeneration and to understand the pathogenesis of IVD degeneration. Clinically, the insights may facilitate future drug development that would benefit millions of patients suffering from low back pain.