Hashimoto K, Mori S, Oda Y, Nakano A, Sawamura T, Akagi M
a Department of Orthopaedic Surgery , Kindai University Faculty of Medicine , Osaka , Japan.
b Department of Bioscience , National Cardiovascular Centre Research Institute , Osaka , Japan.
Scand J Rheumatol. 2016 Oct;45(5):412-22. doi: 10.3109/03009742.2015.1135979. Epub 2016 Feb 22.
The lectin-like oxidized low density lipoprotein (ox-LDL) receptor 1 (LOX-1)/ox-LDL system, which contributes to the pathogenesis of atherosclerosis, may be involved in the development of osteoarthritis (OA). However, the mechanisms by which the LOX-1/ox-LDL system contributes to OA development in vivo are unclear. In this study, we investigated the direct involvement of LOX-1/ox-LDL in OA development by using LOX-1-knockout (LOX-1(-)/(-)) mice in a joint instability-induced model of OA.
OA development was evaluated with histological scoring at 4 and 8 weeks after surgery to induce knee destabilization in LOX-1(+)/(+) and LOX-1(-)/(-) mice. Immunohistological analysis was used to evaluate the expression of LOX-1, ox-LDL, Runt-related transcription factor 2 (Runx2), and type X collagen (COL X) in articular chondrocytes and osteophyte-forming cells. In addition, double immunofluorescence staining was performed to determine the relationships between LOX-1 and Runx2 or COL X expression.
In the model of knee destabilization, symptoms were significantly suppressed in LOX-1(-)/(-) mice. LOX-1, ox-LDL, Runx2, and COL X were overexpressed in articular chondrocytes and osteophyte-forming cells in LOX-1(+)/(+) mice and were significantly downregulated in articular chondrocytes and osteophyte-forming cells in LOX-1(-)/(-) mice compared with those in LOX-1(+)/(+) mice. Double immunostaining indicated that LOX-1 localization coincided with Runx2 and COL X expression.
These data indicate that the LOX-1/ox-LDL system plays a pivotal role in the pathogenesis of instability-induced OA through endochondral ossification. LOX-1-positive chondrocytes and osteophyte-forming cells may be possible targets to prevent disease progression in OA.
凝集素样氧化低密度脂蛋白（ox-LDL）受体1（LOX-1）/ox-LDL系统参与动脉粥样硬化的发病机制，可能也与骨关节炎（OA）的发展有关。然而，LOX-1/ox-LDL系统在体内促进OA发展的机制尚不清楚。在本研究中，我们通过在关节不稳定诱导的OA模型中使用LOX-1基因敲除（LOX-1(-)/(-)）小鼠，研究了LOX-1/ox-LDL在OA发展中的直接作用。
在诱导LOX-1(+)/(+)和LOX-1(-)/(-)小鼠膝关节不稳定的手术后4周和8周，通过组织学评分评估OA的发展。免疫组织学分析用于评估关节软骨细胞和骨赘形成细胞中LOX-1、ox-LDL、 runt相关转录因子2（Runx2）和X型胶原（COL X）的表达。此外，进行双重免疫荧光染色以确定LOX-1与Runx2或COL X表达之间的关系。
在膝关节不稳定模型中，LOX-1(-)/(-)小鼠的症状明显得到抑制。与LOX-1(+)/(+)小鼠相比，LOX-1(+)/(+)小鼠的关节软骨细胞和骨赘形成细胞中LOX-1、ox-LDL、Runx2和COL X过表达，而LOX-1(-)/(-)小鼠的关节软骨细胞和骨赘形成细胞中这些蛋白明显下调。双重免疫染色表明，LOX-1的定位与Runx2和COL X的表达一致。
这些数据表明，LOX-1/ox-LDL系统通过软骨内成骨在不稳定诱导的OA发病机制中起关键作用。LOX-1阳性软骨细胞和骨赘形成细胞可能是预防OA疾病进展的潜在靶点。
