A类清道夫受体I/II型决定抗原诱导性关节炎中基质金属蛋白酶介导的软骨破坏和软骨细胞死亡。

Scavenger receptor class A type I/II determines matrix metalloproteinase-mediated cartilage destruction and chondrocyte death in antigen-induced arthritis.

作者信息

van Lent P L E M, Hofkens W, Blom A B, Grevers L, Sloetjes A, Takahashi N, van Tits L J, Vogl T, Roth J, de Winther M P, van den Berg W B

机构信息

Department of Rhumatology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.

出版信息

Arthritis Rheum. 2009 Oct;60(10):2954-65. doi: 10.1002/art.24908.

DOI:10.1002/art.24908

PMID:19790077

Abstract

OBJECTIVE

Scavenger receptor class A type I (SR-AI) and SR-AII are expressed by macrophages in particular and bind and internalize a broad range of molecules (including endotoxins, apoptotic bodies, and oxidized low-density lipoprotein). This study was undertaken to investigate the role of SR-AI/II in mediating severe cartilage destruction in antigen-induced arthritis (AIA).

METHODS

AIA was induced in the knee joints of SR-AI/II(-/-) mice and wild-type (WT) controls. Joint inflammation and cartilage destruction (chondrocyte death) were measured by examining the histology of total knee joints. Matrix metalloproteinase (MMP)-mediated neoepitopes were measured by immunolocalization using anti-VDIPEN antibodies and chondrocyte activation with anti-S100A8 antibodies. Messenger RNA (mRNA) levels were determined in inflamed synovium using microarray analysis and quantitative reverse transcriptase-polymerase chain reaction. In synovial washouts, cytokines (interleukin-1beta [IL-1beta], IL-10, and tumor necrosis factor alpha) and S100A8/S100A9 were measured using Luminex and enzyme-linked immunosorbent assay.

RESULTS

Levels of SR-AI/II mRNA were strongly elevated in inflamed synovium in AIA. On days 2, 8, and 14 after AIA induction, joint inflammation (exudates/infiltrate) was similar between the 2 groups. In WT mice, severe cartilage destruction was found in multiple cartilage surfaces of the inflamed knee joint on day 14 after AIA induction. MMP-mediated matrix destruction ranged between 40% and 60%, and chondrocyte death was prominent in 40-75% of the cartilage surfaces. In striking contrast, in SR-AI/II(-/-) mice, despite comparable joint inflammation, pronounced cartilage destruction was almost completely absent. Levels of IL-1beta and S100A8/S100A9 were significantly lower on days 7 and 14 after AIA induction, but levels of mRNA for various MMPs (MMP-2, MMP-3, MMP-9, and MMP-13) were comparable.

CONCLUSION

Our findings indicate that SR-AI and SR-AII are crucial receptors involved in mediating severe cartilage destruction in AIA.

摘要

目的

I 型清道夫受体 A 类（SR-AI）和 SR-AII 主要由巨噬细胞表达，可结合并内化多种分子（包括内毒素、凋亡小体和氧化型低密度脂蛋白）。本研究旨在探讨 SR-AI/II 在介导抗原诱导性关节炎（AIA）中严重软骨破坏的作用。

方法

在 SR-AI/II(-/-)小鼠和野生型（WT）对照小鼠的膝关节中诱导 AIA。通过检查全膝关节的组织学来测量关节炎症和软骨破坏（软骨细胞死亡）。使用抗 VDIPEN 抗体通过免疫定位测量基质金属蛋白酶（MMP）介导的新表位，并用抗 S100A8 抗体测量软骨细胞活化。使用微阵列分析和定量逆转录聚合酶链反应测定炎症滑膜中的信使核糖核酸（mRNA）水平。在滑膜灌洗液中，使用 Luminex 和酶联免疫吸附测定法测量细胞因子（白细胞介素-1β [IL-1β]、IL-10 和肿瘤坏死因子α）以及 S100A8/S100A9。

结果

AIA 炎症滑膜中 SR-AI/II mRNA 水平显著升高。在 AIA 诱导后第 2、8 和 14 天，两组之间的关节炎症（渗出物/浸润）相似。在 WT 小鼠中，AIA 诱导后第 14 天，在炎症膝关节的多个软骨表面发现严重软骨破坏。MMP 介导的基质破坏范围在 40%至 60%之间，40 - 75%的软骨表面出现明显的软骨细胞死亡。与之形成鲜明对比的是，在 SR-AI/II(-/-)小鼠中，尽管关节炎症程度相当，但几乎完全没有明显的软骨破坏。AIA 诱导后第 7 天和第 14 天，IL-1β和 S100A8/S100A9 水平显著降低，但各种 MMP（MMP-2、MMP-3、MMP-9 和 MMP-13）的 mRNA 水平相当。