Duloxetine, a selective serotonin-norepinephrine reuptake inhibitor, is currently recommended to use in the treatment of chronic painful disorders such as fibromyalgia, chronic musculoskeletal pain and diabetic peripheral neuropathy. We previously demonstrated that bone morphogenetic protein-4 (BMP-4) stimulates osteoprotegerin (OPG) production in osteoblast-like MC3T3-E1 cells, and that p70 S6 kinase positively regulates the OPG synthesis. The present study is aimed to investigate the effect of duloxetine on BMP-4-stimulated OPG synthesis in these cells. Duloxetine dose-dependently suppressed the OPG release stimulated by BMP-4. Fluvoxamine, a selective serotonin reuptake inhibitor (SSRI), reduced the BMP-4-stimulated OPG release, whereas a selective and specific norepinephrine reuptake inhibitor, reboxetine failed to affect the OPG release. In addition, another SSRI sertraline also inhibited the BMP-4-stimulated OPG release. On the other hand, siRNA of SMAD1 reduced the OPG release stimulated by BMP-4, indicating the involvement of SMAD1/5/8 pathway in the OPG release. Rapamycin, an inhibitor of mTOR, reduced the BMP-4-stimulated p70 S6 kinase phosphorylation, and compound C, an inhibitor of BMP type I receptor, suppressed the SMAD1/5/8 phosphorylation stimulated by BMP-4. Duloxetine did not affect the BMP-4-induced phosphorylation of p70 S6 kinase but suppressed the SMAD1/5/8 phosphorylation. Both fluvoxamine and sertraline also inhibited the BMP-4-elicited phosphorylation of SMAD1/5/8. These results strongly suggest that duloxetine suppresses the BMP-4-stimulated OPG release via inhibition of the Smad1/5/8 signaling pathway from osteoblasts.
A case report: ‘happy heart’ syndrome in a patient treated with atomoxetine for attention deficit hyperactivity disorder