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

Abstract

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.

• Authors: Junko Tachi, Takashi Onuma, Shinobu Yamaguchi, Woo Kim, Tomoyuki Hioki, Rie Matsushima-Nishiwaki, Kumiko Tanabe, Haruhiko Tokuda, Osamu Kozawa, Hiroki Iida
• Journal: Biochemistry and cell biology = Biochimie et biologie cellulaire (Biochem Cell Biol) Vol. 99 Issue 5 Pg. 578-586 (10 2021) ISSN: 1208-6002 [Electronic] Canada
• PMID: 33646885 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Bmp4 protein, mouse
• Bone Morphogenetic Protein 4
• Osteoprotegerin
• Smad1 Protein
• Smad1 protein, mouse
• Smad5 Protein
• Smad5 protein, mouse
• Smad8 Protein
• Smad9 protein, mouse
• Duloxetine Hydrochloride

Topics

• 3T3 Cells
• Animals
• Bone Morphogenetic Protein 4 (antagonists & inhibitors, metabolism)
• Cells, Cultured
• Dose-Response Relationship, Drug
• Duloxetine Hydrochloride (pharmacology)
• Mice
• Osteoblasts (drug effects, metabolism)
• Osteoprotegerin (antagonists & inhibitors, metabolism)
• Signal Transduction (drug effects)
• Smad1 Protein (antagonists & inhibitors, metabolism)
• Smad5 Protein (antagonists & inhibitors, metabolism)
• Smad8 Protein (antagonists & inhibitors, metabolism)