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Duloxetine strengthens osteoblast activation by prostaglandin E1: Upregulation of p38 MAP kinase
ProstaglandIns & Other Lipid Mediators ( IF 2.5 ) Pub Date : 2020-09-28 , DOI: 10.1016/j.prostaglandins.2020.106481
Junko Tachi 1 , Haruhiko Tokuda 2 , Takashi Onuma 3 , Shinobu Yamaguchi 3 , Woo Kim 1 , Tomoyuki Hioki 4 , Rie Matsushima-Nishiwaki 5 , Kumiko Tanabe 3 , Osamu Kozawa 5 , Hiroki Iida 3
Affiliation  

Duloxetine, a serotonin-norepinephrine reuptake inhibitor, is currently recommended as a useful medicine to chronic pain including low back pain. However, as the analogy of classical selective serotonin reuptake inhibitors, there is a concern to deteriorate osteoporosis with remaining to clarify the exact mechanism of duloxetine in bone metabolism. We have previously reported that prostaglandin E1 (PGE1) induces the synthesis of both osteoprotegerin (OPG) and interleukin-6 (IL-6), essential regulators of bone metabolism, in osteoblast-like MC3T3-E1 cells. Based upon them, we herein investigated the mechanism whereby the effect of duloxetine on the synthesis of OPG and IL-6 induced by PGE1 in these cells. Duloxetine enhanced the release from MC3T3-E1 cells of both OPG and IL-6 stimulated by PGE1. However, reboxetine, a selective and specific inhibitor of norepinephrine reuptake, failed to affect the PGE1-induced release of OPG or IL-6. Oppositely, fluvoxamine and sertraline, agents belonging to the class of selective serotonin reuptake inhibitor, upregulated the PGE1-stimulated release of both OPG and IL-6. Duloxetine amplified the expression of OPG mRNA and IL-6 mRNA stimulated by PGE1. Duloxetine strengthened the PGE1-induced p38 MAP kinase phosphorylation, which was amplified by fluvoxamine as well. SB203880, an inhibitor of p38 MAP kinase, suppressed the amplifying effects by duloxetine or fluvoxamine on the PGE1-stimulated release of OPG and IL-6. These results strongly suggest that duloxetine could strengthen osteoblast activation by PGE1 through the upregulation of p38 MAP kinase, leading to increasing the synthesis of OPG and IL-6.



中文翻译:


度洛西汀通过前列腺素 E1 增强成骨细胞活化:上调 p38 MAP 激酶



度洛西汀是一种血清素-去甲肾上腺素再摄取抑制剂,目前被推荐作为治疗慢性疼痛(包括腰痛)的有用药物。然而,与经典的选择性血清素再摄取抑制剂的类比一样,人们担心度洛西汀会恶化骨质疏松症,但仍有待阐明度洛西汀在骨代谢中的确切机制。我们之前报道过,前列腺素 E 1 (PGE 1 ) 诱导成骨细胞样 MC3T3-E1 细胞中骨保护素 (OPG) 和白细胞介素 6 (IL-6) 的合成,这两种物质是骨代谢的重要调节剂。在此基础上,我们研究了度洛西汀对这些细胞中PGE 1诱导的OPG 和IL-6 合成的影响的机制。 Duloxetine 增强了 PGE 1刺激下的 MC3T3-E1 细胞中 OPG 和 IL-6 的释放。然而,瑞波西汀(一种去甲肾上腺素再摄取的选择性和特异性抑制剂)未能影响 PGE 1诱导的 OPG 或 IL-6 释放。相反,氟伏沙明和舍曲林(属于选择性血清素再摄取抑制剂类药物)上调 PGE 1刺激的 OPG 和 IL-6 释放。度洛西汀放大了PGE 1刺激的OPG mRNA 和IL-6 mRNA 的表达。度洛西汀增强了 PGE 1诱导的 p38 MAP 激酶磷酸化,氟伏沙明也增强了这种磷酸化。 SB203880 是一种 p38 MAP 激酶抑制剂,可抑制度洛西汀或氟伏沙明对 PGE 1刺激的 OPG 和 IL-6 释放的放大作用。 这些结果强烈表明,度洛西汀可以通过上调 p38 MAP 激酶来增强 PGE 1对成骨细胞的激活,从而增加 OPG 和 IL-6 的合成。

更新日期:2020-09-28
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