Coordinated existence of multiple gangliosides is required for cartilage metabolism.
Coordinated existence of multiple gangliosides is required for cartilage metabolism.
复制标题
软骨代谢需要多种神经节苷脂的协调存在。
DOI：
10.1016/j.joca.2018.11.003
复制
发表时间：
2019
影响因子：
7
通讯作者：
Iwasaki Norimasa.
中科院分区：
文献类型：
--
作者：
Momma Daisuke;Onodera Tomohiro;Homan Kentaro;Matsubara Shinji;Sasazawa Fumio;Furukawa Junichi;Matsuoka Masatake;Yamashita Tadashi;Iwasaki Norimasa.
神经节苷脂是一种广泛存在的调节跨膜信号传导并介导细胞与细胞和细胞与基质相互作用的膜组分，是炎症和神经系统疾病的关键分子。然而，神经节苷脂在软骨降解过程中的功能仍不清楚。我们研究了神经节苷脂在与骨关节炎（OA）发病机制相关的软骨代谢中的功能作用。设计我们通过靶向β1，4-N-乙酰半乳糖胺转移酶（GalNAcT）基因（编码主要神经节苷脂合成的酶）和GD 3合成酶（GD 3S）基因来产生敲除（KO）小鼠，通过体内OA和体外软骨降解模型评价神经节苷脂对软骨降解的影响结果GalNAcT和GD 3SKO小鼠生长发育正常，但随着年龄的增长，OA的变化加剧。GalNAcTKO小鼠在体内显示出与GD 3Smice相比显著增强的OA进展。GalNAcT和GD 3SKO小鼠均表现出严重的IL-1α诱导的离体软骨降解。IL-1α刺激后，GalNAcT和GD 3SKO中MAPK磷酸化均增强。GalNAcTorGD 3S调控的神经节苷脂可逆转IL-1α诱导的GalNAcTorGD 3S缺失小鼠骨关节炎MMP-13表达的增加。此外，GalNAcT调节的神经节苷脂对软骨代谢很重要，这表明GalNAcT是开发新的OA治疗的潜在靶分子。
ObjectiveGangliosides, ubiquitously existing membrane components that modulate transmembrane signaling and mediate cell-to-cell and cell-to-matrix interactions, are key molecules of inflammatory and neurological disorders. However, the functions of gangliosides in the cartilage degradation process remain unclear. We investigated the functional role of gangliosides in cartilage metabolism related to osteoarthritis (OA) pathogenesis.DesignWe generated knockout (KO) mice by targeting the β1, 4-N-acetylgalactosaminyltransferase (GalNAcT) gene, which encodes an enzyme of major gangliosides synthesis, and the GD3 synthase (GD3S) gene, which encodes an enzyme of partial gangliosides synthesis.In vivoOA andin vitrocartilage degradation models were used to evaluate the effect of gangliosides on the cartilage degradation process.ResultsTheGalNAcTandGD3SKO mice developed and grew normally; nevertheless, OA changes in these mice were enhanced with aging. TheGalNAcTKO mice showed significantly enhanced OA progression compared toGD3Smicein vivo. BothGalNAcTandGD3SKO mice showed severe IL-1α–induced cartilage degradationex vivo. Phosphorylation of MAPKs was enhanced in bothGalNAcTandGD3SKOs after IL-1α stimulation. Gangliosides modulated byGalNAcTorGD3Srescued an increase of MMP-13 induced by IL-1α in mice lackingGalNAcTorGD3Safter exogenous replenishmentin vitro.ConclusionThese data show that the deletion of gangliosides in mice enhanced OA development. Moreover, the gangliosides modulated byGalNAcTare important for cartilage metabolism, suggesting thatGalNAcTis a potential target molecule for the development of novel OA treatments.