以MMPs为靶点的SDF-1/CXCR4信号通路在椎间盘软骨终板和髓核退变中的作用和机制研究

细胞外基质降解是椎间盘软骨终板和髓核退变的主要表现之一，基质金属蛋白酶(MMPs)是其中的关键酶，但是其确切的调控通路尚未完全阐明，阻碍了生物学修复治疗椎间盘退变性疾病的发展。软骨终板与关节软骨一致均为透明软骨，而髓核中的基质成分和细胞生物学特性与关节软骨极为相似。研究表明以MMPs为靶点的SDF-1/CXCR4通路在关节软骨退变中起重要作用，阻断该通路能延缓体内关节软骨ECM的降解，而其在终板软骨和髓核退变中的作用迄今尚未见报道。我们的前期实验发现软骨终板和髓核中均存在SDF-1和CXCR4表达，且退变组的表达水平显著高于正常组。在此基础上，本课题拟采用分子生物学技术、椎间盘器官培养及动物体内实验，研究软骨终板和髓核中以MMPs为靶点的SDF-1/CXCR4通路的调控作用，以及阻断该通路对椎间盘退变的缓解作用。本课题将从新的视角揭示椎间盘退变的发生和发展机制，为其生物学修复提供新的靶点。

The overexpression of matrix metalloproteinases (MMPs), leading to the degradation of extracellular matrix (ECM), is one possible major cause of degenerative cartilage end-plate and nucleus pulposus. However, the molecular mechanism has not yet been studied thoroughly. Cartilage end-plate and articular cartilage are both hyaline cartilage structures. The structural and functional are both similar between chondrocytes in articular cartilage and nucleus pulposus cells. ECM of cartilage end-plate and nucleus pulposus, includes proteoglycan and collagen type II, gradually degrade and the replacement of type I collagen during the process of degeneration. The SDF-1/CXCR4 (stromal cell-derived factor-1/CXC chemokine receptor type 4) pathway targeting MMPs is important in the degeneration of articular cartilage. Blocking this pathway can delay ECM degradation of articular cartilage in vivo, and its role in the endplate cartilage and nucleus pulposus degeneration has not been reported to date. The results of our previous study revealed the existence of SDF-1 and CXCR4 in degenerative discs and their expression levels of degeneration group were significantly higher than those of normal group. We postulated that the SDF-1/CXCR4 pathway also plays a significant role in disc degeneration. For this hypothesis, we plan to investigate the gene and protein expression patterns of SDF-1 and CXCR4 in normal and degenerative discs. Then the expression levels of key MMPs (MMP-1,-3,and-13) as a function of SDF-1/CXCR4 pathway in nucleus pulpsus cells and end plate cartilage cells will be both studied in vitro (cell culture and disc organ culture) to elucidate the intrinsic factor of disc degeneration. The protection or even reverse of degenerative disc will be carried out by inhibition of SDF-1/CXCR4 pathway using RNA interfere technology in vivo. This study will provide profound insights of the mechanism of disc degeneration and thus develop new technology to prevent and treat this disease.