iPTH调控终板内Slit3在椎间盘源性下腰痛中的作用及机制研究

下腰痛作为常见病、多发病，是成人劳动力丧失的第三大原因。研究显示，在椎间盘退变过程中，终板骨硬化和感觉神经异常长入早于髓核退变；而终板骨硬化过程，破骨细胞分泌轴突募集因子Netrin-1介导的感觉神经长入是其病理基础之一。因此，重塑发生骨硬化的软骨终板，抑制感觉神经的长入，是治疗椎间盘源性下腰痛的关键。申请人前期研究发现，使用间歇性甲状旁腺激素（iPTH）对椎间盘退变动物模型进行治疗，可重塑骨硬化终板，同时提升终板内轴突排斥因子Slit3的表达，显著减少终板内神经轴突数量，有效缓解下腰痛行为学异常。本项目拟进一步通过转基因小鼠及恒河猴大动物标本，阐明成骨细胞分泌Slit3参与iPTH治疗后平衡Netrin-1，抑制骨硬化终板内神经长入的药理作用；同时通过体外实验明确iPTH促进成骨细胞分泌Slit3的信号通路，揭示iPTH治疗椎间盘源性下腰痛的分子机制，为其应用于临床治疗奠定基础。

Low back pain (LBP), as a common disease, is the third leading cause of work loss. We previously found that during intervertebral disc degeneration, endplate sclerosis and abnormal sensory nerves innervation occur earlier than nucleus pulposus degeneration. And that osteoclasts derived axon attraction factor Netrin-1 mediates sensory nerve growth during endplate sclerosis, which may be the the basic pathogenesis of LBP. Thus, in the process of intervertebral disc degeneration, how to prevent or remodel the bone sclerosis of the cartilage endplate, balance the attraction/rejection factors of axon ingrowth, and inhibit the sensory innervation are the key issues in the treatment of intervertebral disc associated non-specific LBP. In addition, the applicant found that iPTH can effectively remodel the sclerotic endplate and meanwhile, significantly increase the expression of local axon rejection factor Slit-3, reduce the number of nerve axons in the endplate, and effectively alleviate the mouse behavioral abnormalities related to LBP. This project intends to use transgenic mice and rhesus monkey animal specimens to clarify that osteoblasts derived Slit3 participates in the balance with Netrin-1 after iPTH treatment, to achieve the inhibition on the sensory axons in the osteosclerotic cartilage endplate. Furthermore, we will apply transcriptome sequencing and biochemical experiments to investigate the signal pathway and molecular mechanism that iPTH promotes osteoblast to secrete Slit3, which provide the fundamental knowledge for the clinical application of iPTH in the treatment of discogenic low back pain.