MIF-CD74信号通过调控MMPs参与软骨终板退变的机制研究

Cartilage endplate (CEP) degeneration has been considered to be a significant cause of lumbar disc degeneration. Matrix metalloproteinases (MMPs) is a key factor that leads to structural abnormality, inhibiting the development of biological therapy for intervertebral disc degeneration. However, the mechanism underlying regulation of MMPs in CEP remains largely unclear. Studies have shown that macrophage migration inhibition factor (MIF) can up-regulate the expression of MMPs and promote the destruction of articular cartilage structure; Inhibition of MIF bioactivity can facilitate the cartilage repair. Our previous study demonstrated that MIF and its receptor CD74 are expressed in the CEP with type I modic changes; MIF can induce the up-regulation of IL-6, 8 and PGE2 in CEP via CD74. This study is conducted to investigate the relationship between the MIF-CD74 signal and CEP degeneration, to clarify the effect of MIF-CD74 signal on the expression and function of MMPs, to determine the molecular regulation mechanism of MIF-CD74 signal by studying several related signal molecules including tyrosine kinase, protein kinase C, AP-1, ERK1/2 and NF-κB. This project is going to prove that the MIF-CD74 singal regulating MMPs is involved in the pathogenesis of intervertebral disc degeneration, and verify that specific blockage of MIF-CD74 signal is beneficial for the repair and regeneration of CEP, providing a new target for biological therapy of intervertebral disc degeneration.

软骨终板（CEP）退变是导致腰椎盘退变的重要原因。基质金属蛋白酶（MMPs）是导致CEP结构改变的关键因素，但其调控通路尚未完全阐明，阻碍了生物治疗椎间盘退变的发展。研究发现，巨噬细胞移动抑制因子（MIF）可以上调MMPs，破坏关节软骨结构，阻断MIF能促进软骨修复，而MIF对CEP内MMPs调控作用尚未见报道。前期发现，MIF和其受体CD74表达于人退变CEP内，MIF通过CD74诱导IL-6、8和PGE2上调。我们拟研究MIF-CD74信号与CEP退变的关系；阐明MIF-CD74信号对CEP内MMPs表达和功能的影响；观察MIF-CD74信号激活或阻断后，相关重要信号途径（络氨酸激酶、蛋白激酶C、AP-1、ERK1/2和NF-kB）的变化。该课题的完成有望揭示MIF-CD74信号调控MMPs参与椎间盘退变机制，阐明特异性的阻断该信号对CEP的修复作用，为椎间盘退变的生物治疗提供新靶点。

软骨终板（CEP）退变是导致腰椎盘退变的重要原因。基质金属蛋白酶（MMPs）是导致CEP结构改变的关键因素，但其调控通路尚未完全阐明，阻碍了生物治疗椎间盘退变的发展。研究发现，巨噬细胞移动抑制因子（MIF）可以上调MMPs，而MIF对CEP内MMPs调控作用尚未见报道。结合前期发现，我们通过对不同退变等级的椎间盘进行分级，发现椎间盘内MIF和MMPs表达与腰椎间盘的退变程度呈正相关；我们的研究结果显示，MIF-CD74信号可通过ERK1/2通路调控其下游的IL-6、IL-8、IL-1β、TNF-α、MMP-1、MMP-3和MMP-13的合成释放，从而在CEP内的基质降解，骨化过程中发挥的关键作用；另外，我们还发现MIF-CD74信号还可以通过调控MMP-1和MMP-3来参与椎间盘内巨噬细胞的迁移过程。该课题的完成有望揭示MIF-CD74信号调控MMPs参与椎间盘退变机制，阐明特异性的阻断该信号对CEP的修复作用，为椎间盘退变的生物治疗提供新靶点。