南方医科大学学报

南方医科大学学报 ›› 2023, Vol. 43 ›› Issue (10): 1776-1781.doi: 10.12122/j.issn.1673-4254.2023.10.16

• • 上一篇    下一篇

大黄素对胶原诱导性关节炎大鼠的骨保护作用:基于抑制铁死亡和降解基质金属蛋白酶

周思聪，杨 威，曾 丽，曹春浩，袁 速，荣晓凤   

  1. 重庆医科大学附属第一医院中西医结合科，重庆 400016
  • 出版日期:2023-10-20 发布日期:2023-11-03

Emodin alleviates joint inflammation and bone erosion in rats with collagen-induced arthritis by inhibiting ferroptosis and degrading matrix metalloproteinases

ZHOU Sicong, YANG Wei, ZENG Li, CAO Chunhao, YUAN Su, RONG Xiaofeng   

  1. Department of Integrated Chinese and Western Medicine, First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
  • Online:2023-10-20 Published:2023-11-03

RichHTML

10

PDF

305

摘要： 目的 探讨大黄素对类风湿关节炎（RA）铁死亡相关信号通路介导的骨保护作用机制。方法 除正常组外，使用200 μL不完全弗氏佐剂乳化的牛二型胶原构建胶原诱导性关节炎（CIA）大鼠的类风湿关节炎模型。21 d后分为正常组（Normal）、模型组（Model）、甲氨蝶呤组（MTX，0.2 mg/kg，3 次/周）、大黄素（Emo）高（80 mg·kg-1·d-1）、低（40 mg·kg-1·d-1）剂量组，10只/组。记录大鼠造模之后的关节炎评分和足趾体积；使用丙二醛（MDA）试剂盒检测组织MDA含量；用番红固绿染色法、苏木精-伊红染色法对踝关节石蜡切片进行染色，光镜下观察大鼠踝关节组织形态学改变；用免疫组织化学法对踝关节切片的基质金属蛋白酶（MMP）3、13进行染色，光镜下观察大鼠踝关节MMPs的表达；Western blot法检测大鼠踝关节组织中长链酯酰辅酶A合成酶4（ACSL4）、溶质载体家族7成员11（SLC7A11）、谷胱甘肽过氧化物酶4（GPX4）、铁蛋白重链1（FTH1）的蛋白质含量。结果 与正常组相比，模型组大鼠的关节炎评分指数、足趾肿胀度增高（P<0.05）；软骨表面粗糙，软骨细胞丢失、排列杂乱稀疏；MDA含量和ACSL4的蛋白质含量升高，SLC7A11、GPX4、FTH1的含量降低（P<0.05）；踝关节MMP3和MMP13的表达量升高；与模型组相比，MTX组和大黄素（40 mg/kg、80 mg/kg）组的关节炎评分指数、足趾肿胀度降低（P<0.05），软骨表面相对光滑平整，软骨细胞排列整齐，MDA含量升高（P<0.05）；MTX组和大黄素高剂量组ACSL4的蛋白质含量降低，SLC7A11、GPX4、FTH1的含量升高（P<0.05）。结论 大黄素能有效控制CIA大鼠关节炎症、改善关节骨侵蚀。调节铁死亡相关信号通路ACSL4、SLC7A11、GPX4、FTH1的含量，降低MMP3和MMP13的表达,可能是其抑制RA骨破坏的重要机制和途径之一。

关键词: 类风湿关节炎；胶原诱导性关节炎大鼠；铁死亡；基质金属蛋白酶；骨破坏

Abstract: Objective To investigate the osteoprotective mechanism of emodin in light of the ferroptosis signaling pathway in a rat model of rheumatoid arthritis. Methods SD rat models of collagen-induced arthritis (CIA) were treated with methotrexate or low or high doses of emodin, and the changes in arthritis scores and toe volume were recorded. model of CIA rats. Malondialdehyde (MDA) content in the joint cartilage was determined, and ankle joint tissue pathologies were observed using caffein solid green staining and hematoxylin-spermine red staining. MMP3 and MMP13 expressions in the ankle joint tissues were detected using immunohistochemistry, and Western blotting was used to detect the protein expressions of ACSL4, SLC7A11, GPX4, and FTH1. Results Compared with the normal control rats, the CIA rats showed significantly increased arthritis score index with obvious toe swelling (P<0.05), rough cartilage surface, and loss and irregular aligment of chondrocytes. The rat models also showed significantly increased MDA and ACSL4 contents, lowered SLC7A11, GPX4, and FTH1 contents (P<0.05), and decreased expressions of MMP3 and MMP13 in the ankle joint (P<0.05). The rat models treated with either methotrexate or emodin (40 and 80 mg/kg) had significantly reduced arthritis score index and toe swelling with smooth cartilage surface and neat arrangement of the chondrocytes. The treatments with methotrexate and emodin both decreased the contents of MDA and ACSL4 and increased the contents of SLC7A11, GPX4, and FTH1 in the joint tissues (P<0.05). Conclusion Emodin can effectively control joint inflammation and improve joint bone erosion in CIA rats possibly by inhibiting the ferroptosis signaling pathways and reducing the expressions of MMP3 and MMP13.

Key words: rheumatoid arthritis; collagen-induced arthritis; ferroptosis; matrix metalloproteinases; bone destruction