Depletion of gangliosides enhances cartilage degradation in mice
Depletion of gangliosides enhances cartilage degradation in mice
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DOI：
10.1016/j.joca.2013.11.015
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发表时间：
2014-02-01
影响因子：
7
通讯作者：
Iwasaki, N.
中科院分区：
文献类型：
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作者：
Sasazawa, F.;Onodera, T.;Iwasaki, N.
目的：鞘糖脂（GSL）是普遍存在的膜成分，在维持软骨细胞稳态中发挥功能作用。我们研究了神经节苷脂（GSL 的主要成分之一）在骨关节炎 (OA) 发病机制中的潜在作用。设计：使用 GM3 合酶敲除 (GM3.5(-/-)) 小鼠生成年龄相关和不稳定诱导的 OA 模型。分析软骨退化模型和瞬时 GM3S 转染的软骨细胞，以评估神经节苷脂在 OA 发展中的功能。使用质谱 (MS) 分析 IL-1 α 刺激后软骨细胞中每个系列 GSL 的量。结果：与野生型 (WT) 小鼠相比，GM3.5(-/-) 小鼠的 OA 变化随着年龄的增长而显着增强。 GM3.5(-/-)小鼠在体内表现出更严重的不稳定诱导的病理性OA。神经节苷脂缺乏还导致体外诱导基质金属蛋白酶 (MMP)-13 和 ADAMTS-5 分泌以及软骨细胞凋亡。相反，软骨细胞的瞬时GM3.5(-/-)转染在白细胞介素(IL)-1α刺激后抑制了MMP-13和ADAMTS-5的表达。 GSL分析显示IL-1α刺激后软骨细胞中存在丰富的神经节苷脂。结论：神经节苷脂通过调节MMP-13和ADAMTS-5的表达以及软骨细胞凋亡在OA发病机制中发挥关键作用。基于所获得的结果，我们提出神经节苷脂是开发新型 OA 治疗的潜在靶分子。 (C) 2013 年国际骨关节炎研究协会。由爱思唯尔有限公司出版。保留所有权利。
Objective: Glycosphingolipids (GSLs) are ubiquitous membrane components that play a functional role in maintaining chondrocyte homeostasis. We investigated the potential role of gangliosides, one of the major components of GSLs, in osteoarthritis (OA) pathogenesis.Design: Both age-associated and instability-induced OA models were generated using GM3 synthase knockout (GM3.5(-/-)) mice. A cartilage degradation model and transiently GM3S-transfected chondrocytes were analyzed to evaluate the function of gangliosides in OA development. The amount of each series of GSLs in chondrocytes after IL-1 alpha stimulation was profiled using mass spectrometry (MS).Results: OA changes in GM3.5(-/-) mice were dramatically enhanced with aging compared to those in wildtype (WT) mice. GM3.5(-/-) mice showed more severe instability-induced pathologic OA in vivo. Ganglioside deficiency also led to the induction of matrix metalloproteinase (MMP)-13 and ADAMTS-5 secretion and chondrocyte apoptosis in vitro. In contrast, transientGM3.5(-/-) transfection of chondrocytes suppressed MMP-13 and ADAMTS-5 expression after interleukin (IL)-1 alpha stimulation. GSL profiling revealed the presence of abundant gangliosides in chondrocytes after IL-1 alpha stimulation.Conclusion: Gangliosides play a critical role in OA pathogenesis by regulating the expression of MMP-13 and ADAMTS-5 and chondrocyte apoptosis. Based on the obtained results, we propose that gangliosides are potential target molecules for the development of novel OA treatments. (C) 2013 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.