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.

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。