Abstract：
Intervertebral disc degeneration (IDD) is associated with low back pain, yet its inherent mechanism remains obscure. Hypercholesteremia was regarded as a risk factor for IDD, and our previous study showed that cholesterol accumulation could elicit matrix degradation in the nucleus pulposus (NP). MicroRNA-155 (miR-155) was substantiated as protective in IDD, but its role in cholesterol-induced IDD was unclear. The present study investigated whether miR-155 could mediate cholesterol-related IDD and its internal mechanisms. In vivo experiments revealed high-fat diet-induced hypercholesteremia in wild-type (WT) mice along with the occurrence of IDD, whereas Rm155LG transgenic mice showed milder NP degeneration, as evidenced by Saffron O-fast green (SF) staining and immunohistochemistry (IHC). Meanwhile, IHC showed that NLRP3 and Bax expression was also suppressed in Rm155LG mice. In vitro studies using Western blotting (WB) and immunofluorescence (IF) confirmed that the miR-155 mimic could alleviate cholesterol-induced matrix degradation, apoptosis and pyroptosis in NP. Moreover, RORα was upregulated in severely degenerated NP compared to mild IDD. It was also noted that RORα was suppressed in Rm155LG mice. In this study, we demonstrated that miR-155 could target RORα and that inhibition of RORα could prevent cholesterol-induced matrix degradation, apoptosis, and pyroptosis in NP, indicating the protective effect of miR-155 in cholesterol-induced IDD by targeting RORα.
摘要：
椎间盘退变（IDD）与下背痛有关，然而其固有机制仍然模糊。高胆固醇血症被认为是IDD的危险因素，我们先前的研究表明，胆固醇的积累可以引起髓核（NP）中基质的降解。MicroRNA-155（miR-155）在IDD中被证实具有保护性，但其在胆固醇诱导的IDD中的作用尚不清楚.本研究调查了miR-155是否可以介导胆固醇相关的IDD及其内在机制。体内实验显示，高脂饮食诱导的野生型（WT）小鼠高胆固醇血症以及IDD的发生，而Rm155LG转基因小鼠表现出轻度的NP变性，如SafraninO-fast绿色（SF）染色和免疫组织化学（IHC）所证明。同时,IHC显示在Rm155LG小鼠中NLRP3和Bax表达也受到抑制。使用Western印迹（WB）和免疫荧光（IF）的体外研究证实，miR-155模拟物可以减轻胆固醇诱导的基质降解，NP中的凋亡和焦亡。此外，与轻度IDD相比，严重退化的NP中RORα上调。还注意到Rm155LG小鼠中RORα被抑制。在这项研究中,我们证明miR-155可以靶向RORα，并且抑制RORα可以防止胆固醇诱导的基质降解，凋亡，和NP的焦亡，表明miR-155通过靶向RORα在胆固醇诱导的IDD中的保护作用。
