Pathological roles of oxidized low-density lipoprotein receptor in rheumatoid arthritis

我们试图在类风湿性关节炎（RA）关节软骨标本中检测氧化低密度脂蛋白（ox-LDL）和凝集素样氧化LDL受体-1 （LOX-1）的存在，并研究ox-LDL与LOX-1的相互作用是否能诱导关节软骨外植体培养中基质金属蛋白酶(MMP)-3。当从RA、骨关节炎（OA）和股骨颈骨折患者获得的人关节软骨标本用共聚焦荧光显微镜检测LOX-1和ox-LDL时，大多数RA软骨细胞被抗LOX-1和抗ox-LDL抗体阳性染色。相比之下，OA和正常软骨标本中未发现阳性细胞。通过免疫荧光分析评估ox-LDL与LOX-1之间的关联时，抗LOX-1抗体抑制了外植体培养中dii标记的ox-LDL与软骨细胞的结合，表明这种相互作用是由LOX-1介导的。将股骨颈骨折患者的关节软骨标本用ox-LDL孵育，用中和性抗LOX-1抗体预孵育，ox-LDL诱导关节软骨细胞合成MMP-3并诱导LOX-1，使MMP-3分泌到培养基中。抗lox -1抗体将ox- ldl刺激的MMP-3合成逆转到控制水平。因此，RA软骨中ox-LDL积累增加，LOX-1表达升高，表明受体-配体相互作用在RA软骨病理中的特定作用。我们的下一个尝试是确定LOX-1的可溶性形式（sLOX-1）在患病关节滑液中的水平。与OA患者相比，RA患者滑液中sLOX-1水平明显升高。在膝关节OA患者中，sLOX-1水平与CRP或ESR无显著相关性。RA滑液中sLOX-1水平与CRP有显著相关性，与ESR无显著相关性。这些结果表明，sLOX-1可能是诊断RA的有用工具和RA活性的生物标志物。少

We attempted to detect the presence of oxidized low-density lipoprotein (ox-LDL) and lectin-like oxidized LDL receptor-1 (LOX-1) in cartilage specimens from rheumatoid arthritis (RA) joints and to investigate whether interaction of ox-LDL with LOX-1 can induce matrix metalloproteinase (MMP)-3 in articular cartilage explant culture. When human articular cartilage specimens obtained from patients with RA, osteoarthritis (OA) and femoral neck fracture were examined with confocal fluorescence microscopy for LOX-1 and ox-LDL, the majority of RA chondrocytes were positively stained with both anti-LOX-1 and anti-ox-LDL antibodies. In contrast, no positive cells were found in OA and normal cartilage specimens. When association between ox-LDL and LOX-1 was evaluated by immunofluorescence analysis, anti-LOX-1 antibody suppressed the binding of DiI-labeled ox-LDL to chondrocytes in explant culture, suggesting that the interaction was mediated by LOX-1. When articular cartilage specimens from pati … More ents with femoral neck fracture were incubated with ox-LDL, with pre-incubation with neutralizing anti-LOX-1 antibody, ox-LDL induced MMP-3 synthesis by articular chondrocytes in association with induction of LOX-1, resulting in enhanced secretion of MMP-3 into the culture media. Anti-LOX-1 antibody reversed ox-LDL-stimulated MMP-3 synthesis to control levels. Thus, increased accumulation of ox-LDL with elevated expression of LOX-1 in RA cartilage indicates a specific role of the receptor-ligand interaction in cartilage pathology in RA.Our next attempt was to determine the levels of soluble form of LOX-1 (sLOX-1) in synovial fluid from diseased joint. The levels of sLOX-1 were significantly increased in RA synovial fluid, in contrast to those in OA. In patients with knee OA, there was no significant correlation between sLOX-1 levels and CRP or ESR. The levels of sLOX-1 in RA synovial fluid significantly correlated with CRP, but not with ESR. These results indicate that sLOX-1 could be a useful tool of diagnosis of RA and a biomarker of RA activity. Less