Duloxetine suppresses BMP-4-induced release of osteoprotegerin via inhibition of the SMAD signaling pathway in osteoblasts

• DOI: 10.1139/bcb-2020-0347
• Publication Date: 2021-03-01T21:35:38Z
• Authors: Junko Tachi; Takashi Onuma; Shinobu Yamaguchi; Woo Kim; Tomoyuki Hioki; Rie Matsushima-Ni...; Kumiko Tanabe; Haruhiko Tokuda; Osamu Kozawa; Hiroki Iida
• Keywords: Smad5 Protein; 0303 health sciences; Osteoblasts; Dose-Response Relationship, Drug; Osteoprotegerin; 3T3 Cells; Bone Morphogenetic Protein 4; Duloxetine Hydrochloride; Smad1 Protein; 3. Good health; Mice; 03 medical and health sciences; Smad8 Protein; Animals; Cells, Cultured; Signal Transduction

Duloxetine, a selective serotonin-norepinephrine reuptake inhibitor, is currently recommended for 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 OPG synthesis. The present study aimed to investigate the effect of duloxetine on BMP-4-stimulated OPG synthesis in these cells. Duloxetine dose-dependently suppressed OPG release stimulated by BMP-4. Fluvoxamine, a selective serotonin reuptake inhibitor (SSRI), reduced BMP-4-stimulated OPG release, whereas a selective and specific norepinephrine reuptake inhibitor, reboxetine, failed to affect OPG release. In addition, another SSRI sertraline also inhibited BMP-4-stimulated OPG release. On the other hand, siRNA of SMAD1 reduced the OPG release stimulated by BMP-4, indicating the involvement of the SMAD1/5/8 pathway in OPG release. Rapamycin inhibited BMP-4-stimulated p70 S6 kinase phosphorylation, and compound C suppressed the SMAD1/5/8 phosphorylation stimulated by BMP-4. Duloxetine did not affect BMP-4-induced phosphorylation of p70 S6 kinase but suppressed SMAD1/5/8 phosphorylation. Both fluvoxamine and sertraline also inhibited BMP-4-elicited phosphorylation of SMAD1/5/8. These results strongly suggest that duloxetine suppresses BMP-4-stimulated OPG release via inhibition of the Smad1/5/8 signaling pathway in osteoblasts.