KU-0063794对老年小鼠脊柱椎间盘退变的保护机制

Protective mechanism of KU-0063794 on spinal disc degeneration in aged mice

目的探讨KU-0063794对老年小鼠脊柱椎间盘退变的保护机制。方法60只老年小鼠被随机分为对照组、10mg／kg组和30mg／kg组。10mg／kg组和30mg／kg组分别经腹腔注射KU-0063794 10mg／kg和30mg／kg，对照组注射等体积生理盐水。连续治疗3个月后，对3组小鼠体重、髓核细胞自噬水平、骨密度、组织学评分和骨形态计量学参数进行分析。结果与对照组[（29.31±2.89）g]比较，10mg/kg组和30mg／kg组小鼠体重[（28.19±2.61）g和（27.19±2.62）g]比较差异无统计学意义（t=0.719，P=0.152；t=0.609，P=0.204）。与对照组小鼠髓核细胞中p62水平（1.14±0.23）比较，10mg／kg组和30mg/kg组小鼠髓核细胞中p62表达水平（0.64±0.21；0.23±0.18）显著下调，差异有统计学意义（t=2.192，P=0.009；t=5.910，P=0.000）。与对照组小鼠骨密度（0.19±0.02）比较，10mg／kg组和30mg/kg组小鼠骨密度（0.24±0.01，0.29±0.02）显著升高，差异有统计学意义（t=2.997，P=0.000；t=4.912，P=0.000）。与对照组小鼠L5～L6椎间盘组织病理评分[（5.24±1.02）分]比较，10mg／kg组和30mg/kg组小鼠L5～L6椎间盘组织病理评分[（3.98±0.89）、（2.32±0.54）分]显著下调，差异有统计学意义（t=3.012，P=0.003：t=5.103.P=0.000）。与对照组比较，10mg／kg组和30mg／kg组小鼠骨形态学计量参数也显著改善。结论KU-0063794通过抑制哺乳动物雷帕霉素靶蛋白（mTOR）活性，显著提高机体自噬水平，促进椎间盘自我更新，达到缓解退变的功能。

Objective To explore the protective mechanism of KU-0063794 on the degeneration of the intervertebral disc in aged mice. Methods 60 senile mice were divided into control group, 10 mg/kg group and 30 mg/kg group. 10 mg/kg group and 30 mg/kg group were injected 10 mg/kg group and 30 mg/kg KU-0063794 by intraperitoneal injection and the control group was injected with equal volume of normal saline. After 3 months of continuous treatment, the body weight, autophagy level, bone mineral density, histological score and bone histomorphometric parameters of three groups of mice were an- alyzed. Results Compared with the control group [（ 29.31±2. 89）g], the weight of the mice in the 10 mg/kg group and the 30 mg/kg group （28.19±2.61） g and （27.19±2.62）g] were not statistically significant （t=0.719, P=0.152; t=0.609, P=0.204）. Compared with the level of p62 （1.14±0.23 ） in the nucleus puiposus cells of the control group, the level of p62 expression in the nucleus pulposus cells of the 10 mg/kg group and the 30 mg/kg group （0.64±0.21; 0.23±0.18） significantly reduced （t=2.192, P=0.009 ; t=5.910, P=0.000）. Compared with the bone mineral density of the control group （0. 19±0. 02）, the bone density （0. 24±0. 01, 0. 29±0. 02） in the 10 mg/kg group and the 30 mg/kg group significantly increased （ t = 2. 997, P = 0. 000; t = 4. 912, P = 0. 000）. Compared with the L5-L6 disc histopathology score of the control group （ 5.24±1.02 ） , the histopathological score of the L5-L6 intervertebral disc in the 10 mg/kg group and the 30 mg/kg group （3.98±0. 89; 2.32±0. 54） was significantly down, and the difference was statistically significant （ t=3.012, P=0.003 ; t=5.103, P=0. 000）. Compared with the control group, the bone morphometric parameters of the 10 mg/kg group and the 30 mg/kg group were also significantly improved. Conclusion KU-0063794 can significantly improve the autophagy level and promote the self renewal of the intervertebral disc by inhibiting the activity of mammalian target of rapamycin （mTOR） , so as to alleviate the degeneration function.