抑制Notch信号通路减少大鼠膝骨关节炎关节软骨内MMP-13的上调和Col Ⅱ的降低

Inhibition of Notch signaling pathway decreases the up-regulation of matrix metalloproteinase-13 and the reduction of type Ⅱ collagen in the rat articular cartilage of knee osteoarthritis

目的研究抑制Notch信号通路对大鼠膝骨关节炎(osteoarthritis,OA)进展的影响。方法以前交叉韧带切断术建立大鼠膝骨关节炎模型,膝关节腔注射Notch信号通路抑制剂(2S)-N-[N-(3,5-二氟苯乙酰基)-L-丙氨酰]-2-苯基甘氨酸叔丁酯{(2S)-N-[N-(3,5-difluorophenacetyl)-L-alanyl]-2-phenylglycine tert-butyl ester,DAPT}进行干预,用HE染色法检测膝骨关节炎组织病理学变化,以免疫组织化学染色分析膝关节软骨内基质金属蛋白-13(matrix metalloproteinases-13,MMP-13)以及Ⅱ型胶原蛋白(type II collagen,Col II)表达情况。结果膝骨关节炎关节软骨出现明显组织学损害,MMP-13免疫反应性明显增强,Ⅱ型胶原蛋白免疫反应性明显降低;膝关节腔注射Notch信号通路抑制剂DAPT明显抑制膝骨关节炎关节软骨的组织学损害、MMP-13免疫反应性的增强和Ⅱ型胶原蛋白免疫反应性的降低。结论抑制Notch信号通路可通过抑制骨关节炎关节软骨内MMP-13水平的上调、减少Ⅱ型胶原蛋白的破坏而减轻骨关节炎。

Objective To investigate the effects o f inhibiting Notch signaling pathway on the progression o f knee osteoarthritis(O A)in rats.Methods The rat knee osteoarthritis model was established through anterior cruciate ligament transection.In the intervention group,Notch signaling pathway inhibitor(2S)-N-[N-(3,5-Difluorophenacetyl)-L-alanyl]-2-phenylglycine tert-butyl ester(DAPT)was injected into knee jo in t cavity.HE staining was used to visualize histopathological changes and immunohistochemistry was used to determine the expression o f m atrix metalloproteinase-13(MMP-13)and type Hcollagen(Col II)in knee jo in t cartilage.Results There were severe histological damages in the articular cartilage o f knee osteoarthritis,in which MMP-13 level significantly increased and Col II level significantly decreased.Injection o f DAPT in knee jo in t not only significantly reversed the histological damages,but reduced the immunoreactivity o f MMP-13 and increased type II collagen in the osteoarthritic articular cartilage.Conclusion Inhibiting Notch signaling pathway reduced knee osteoarthritis by decreasing MMP-13 expression and Col II loss in rats.