High LDL levels lead to increased synovial inflammation and accelerated ectopic bone formation during experimental osteoarthritis
High LDL levels lead to increased synovial inflammation and accelerated ectopic bone formation during experimental osteoarthritis
复制标题
DOI：
10.1016/j.joca.2015.11.016
复制
发表时间：
2016-05-01
影响因子：
7
通讯作者：
van Lent, P. L.
中科院分区：
文献类型：
--
作者：
de Munter, W.;van den Bosch, M. H.;van Lent, P. L.
目的：骨关节炎（OA）与胆固醇升高之间的关系是显而易见的。在本研究中，我们研究了载脂蛋白E (ApoE)（-/-）小鼠在有和没有高胆固醇饮食的情况下的OA病理，这是一种独立于体重的高系统性低密度脂蛋白（LDL）胆固醇水平的模型。方法：野生型（WT）、Apoe（-/-）、S100a9（-/-）和Apoe(-/-) S100a9（-/-）小鼠（C57BL/6背景）给予标准或富含胆固醇的饮食。采用关节内注射胶原酶诱导实验性OA，分别于第10天和第36天处死动物。结果：尽管在WT和ApoE（-/-）小鼠之间发现软骨损伤的微小差异，但后者发现滑膜增厚增加。OA诱导后36天，ApoE（-/-）小鼠在标准饮食中显示异位骨形成增加，特别是在内侧副韧带，与OA WT小鼠相比。此外，在ApoE（-/-）小鼠中，S100a8和S100a9以及S100a8 / S100a9蛋白水平的滑膜基因表达显著增加，表明滑膜细胞处于激活的炎症状态。在ApoE（-/-）和WT小鼠中，添加富含胆固醇的饮食导致骨性关节炎晚期内侧副韧带过度骨形成。有趣的是，在早期时间点，与WT小鼠相比，ApoE（-/-）小鼠的蛋白多糖沉积已经显著增加。ApoE和S100a9缺失的小鼠也表现出异位骨形成增加，但滑膜激活不增加，这表明s100蛋白在胆固醇介导的滑膜激活中起作用。结论：胆固醇水平升高可显著提高早期胶原酶诱导OA的滑膜活化和异位骨形成。(c) 2015年国际骨关节炎研究学会。Elsevier Ltd.出版。版权所有。
Objective: A relation between osteoarthritis (OA) and increased cholesterol levels is apparent. In the present study we investigate OA pathology in apolipoprotein E (ApoE)(-/-) mice with and without a cholesterol-rich diet, a model for high systemic low density lipoprotein (LDL) cholesterol levels independent of weight.Method: Wild type (WT), Apoe(-/-), S100a9(-/-) and Apoe(-/-) S100a9(-/-) mice (C57BL/6 background) received a standard or cholesterol-rich diet. Experimental OA was induced by intra-articular injection of collagenase and animals were sacrificed at day 10 and day 36.Results: Although minimal differences in cartilage damage were found between the WT and ApoE(-/-) mice, increased synovial thickening was found in the latter. Thirty-six days after OA-induction, ApoE(-/-) mice on a standard diet showed increased ectopic bone formation, particularly at the medial collateral ligament, compared with OA in WT mice. Furthermore, a significant increase in synovial gene expression of both S100a8 and S100a9 and S100A8/S100A9 protein levels was found in ApoE(-/-) mice, suggesting an activated inflammatory status of synovial cells. In both ApoE(-/-) and WT mice, addition of a cholesterol-rich diet resulted in excessive bone formation in the medial collateral ligament at late-time-point OA. Interestingly, at the early time point, proteoglycan deposition was already significantly increased in ApoE(-/-) mice compared with WT mice. Mice deficient for both ApoE and S100a9 also showed increased ectopic bone formation, but not synovial activation, suggesting a role for S100-proteins in cholesterol-mediated synovial activation.Conclusions: Increased cholesterol levels strongly elevate synovial activation and ectopic bone formation in early-stage collagenase-induced OA. (c) 2015 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.