Cyclic phosphatidic acid and lysophosphatidic acid induce hyaluronic acid synthesis via CREB transcription factor regulation in human skin fibroblasts
Cyclic phosphatidic acid and lysophosphatidic acid induce hyaluronic acid synthesis via CREB transcription factor regulation in human skin fibroblasts
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DOI：
10.1016/j.bbalip.2014.05.004
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发表时间：
2014-09-01
影响因子：
4.8
通讯作者：
Murakami-Murofushi, Kimiko
中科院分区：
文献类型：
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作者：
Maeda-Sano, Katsura;Gotoh, Mari;Murakami-Murofushi, Kimiko
环磷脂酸(CPA)是一种天然存在的磷脂介质，是生长因子样磷脂溶血磷脂酸(LPA)的类似物。CPA在其甘油骨架的sn-2和sn-3位置上有一个独特的环状磷酸环。在此之前，我们发现一种代谢稳定的CPA衍生物2-Carba-CPA在体内可以缓解骨关节炎的发病，并在体外诱导人骨关节炎滑膜细胞合成透明质酸。这项研究的重点是人成纤维细胞中透明质酸的合成，透明质酸在真皮中保持水分和保持健康。我们研究了CPA和LPA对人成纤维细胞(NB1RGB细胞)透明质酸合成的影响。通过颗粒排除法和酶联免疫吸附试验，我们发现CPA和LPA都能诱导透明质酸的合成，并呈剂量依赖关系。我们发现CPA和LPA处理后透明质酸合成酶2信使RNA和蛋白的表达呈时间依赖性地上调。然后，我们在NB1RGB细胞中鉴定了CPA和LPA介导的上调透明质酸合成的信号通路。药理抑制和报告基因分析表明，CPA和LPA作用于NB1RGB细胞后，LPA受体LPAR(1)、G(I/o)、蛋白、磷脂酰肌醇-3激酶(PI3K)、细胞外信号调节蛋白(ERK)和环磷酸腺苷反应元件结合蛋白(CREB)的激活可诱导透明质酸合成，而核因子kappa B不能诱导透明质酸的合成。这些结果首次证明CPA和LPA主要通过激活LPAR(1)-G(i/o)，其次是PI3K、ERK和CREB信号通路来诱导人皮肤成纤维细胞合成透明质酸。(C)2014年提交人。爱思唯尔出版公司(Elsevier B.V.)
Cyclic phosphatidic acid (cPA) is a naturally occurring phospholipid mediator and an analog of the growth factor-like phospholipid lysophosphatidic acid (LPA). cPA has a unique cyclic phosphate ring at the sn-2 and sn-3 positions of its glycerol backbone. We showed before that a metabolically stabilized cPA derivative, 2-carba-cPA, relieved osteoarthritis pathogenesis in vivo and induced hyaluronic acid synthesis in human osteoarthritis synoviocytes in vitro. This study focused on hyaluronic acid synthesis in human fibroblasts, which retain moisture and maintain health in the dermis. We investigated the effects of cPA and LPA on hyaluronic acid synthesis in human fibroblasts (NB1RGB cells). Using particle exclusion and enzyme-linked immunosorbent assays, we found that both cPA and LPA dose-dependently induced hyaluronic acid synthesis. We revealed that the expression of hyaluronan synthase 2 messenger RNA and protein is up-regulated by cPA and LPA treatment time dependently. We then characterized the signaling pathways up-regulating hyaluronic acid synthesis mediated by cPA and LPA in NB1RGB cells. Pharmacological inhibition and reporter gene assays revealed that the activation of the LPA receptor LPAR(1), G(i/o), protein, phosphatidylinositol-3 kinase (PI3K), extracellular-signal-regulated kinase (ERK), and cyclic adenosine monophosphate response element-binding protein (CREB) but not nuclear factor kappa B induced hyaluronic acid synthesis by the treatment with cPA and LPA in NB1RGB cells. These results demonstrate for the first time that cPA and LPA induce hyaluronic acid synthesis in human skin fibroblasts mainly through the activation of LPAR(1)-G(i/o), followed by the PI3K, ERK, and CREB signaling pathway. (C) 2014 The Authors. Published by Elsevier B.V.