Duloxetine strengthens osteoblast activation by prostaglandin E 1 : Upregulation of p38 MAP kinase

• Published in: Prostaglandins & other lipid mediators 2020-12, Vol.151, p.106481
• Main Authors: Tachi, Junko, Tokuda, Haruhiko, Onuma, Takashi, Yamaguchi, Shinobu, Kim, Woo, Hioki, Tomoyuki, Matsushima-Nishiwaki, Rie, Tanabe, Kumiko, Kozawa, Osamu, Iida, Hiroki
• Format: Article
• Language: English
• Subjects: Alprostadil - analogs & derivatives; Alprostadil - pharmacology; Animals; Cell Line; Duloxetine Hydrochloride - pharmacology; Fluvoxamine - pharmacology; Interleukin-6 - genetics; Interleukin-6 - metabolism; Mice; Osteoblasts - drug effects; Osteoblasts - metabolism; Osteoprotegerin - genetics; Osteoprotegerin - metabolism; p38 Mitogen-Activated Protein Kinases - metabolism; Sertraline - pharmacology; Up-Regulation - drug effects
• ISSN: 1098-8823
• DOI: 10.1016/j.prostaglandins.2020.106481

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 E (PGE ) 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 PGE in these cells. Duloxetine enhanced the release from MC3T3-E1 cells of both OPG and IL-6 stimulated by PGE . However, reboxetine, a selective and specific inhibitor of norepinephrine reuptake, failed to affect the PGE -induced release of OPG or IL-6. Oppositely, fluvoxamine and sertraline, agents belonging to the class of selective serotonin reuptake inhibitor, upregulated the PGE -stimulated release of both OPG and IL-6. Duloxetine amplified the expression of OPG mRNA and IL-6 mRNA stimulated by PGE . Duloxetine strengthened the PGE -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 PGE -stimulated release of OPG and IL-6. These results strongly suggest that duloxetine could strengthen osteoblast activation by PGE through the upregulation of p38 MAP kinase, leading to increasing the synthesis of OPG and IL-6.