{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,28]],"date-time":"2026-02-28T19:39:48Z","timestamp":1772307588183,"version":"3.50.1"},"reference-count":41,"publisher":"Canadian Science Publishing","issue":"5","license":[{"start":{"date-parts":[[2021,10,1]],"date-time":"2021-10-01T00:00:00Z","timestamp":1633046400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/www.nrcresearchpress.com\/page\/about\/CorporateTextAndDataMining"}],"content-domain":{"domain":["cdnsciencepub.com"],"crossmark-restriction":false},"short-container-title":["Biochem. Cell Biol."],"published-print":{"date-parts":[[2021,10]]},"abstract":"<jats:p> 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. <\/jats:p>","DOI":"10.1139\/bcb-2020-0347","type":"journal-article","created":{"date-parts":[[2021,3,1]],"date-time":"2021-03-01T21:35:38Z","timestamp":1614634538000},"page":"578-586","update-policy":"https:\/\/doi.org\/10.1139\/csp-crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["Duloxetine suppresses BMP-4-induced release of osteoprotegerin via inhibition of the SMAD signaling pathway in osteoblasts"],"prefix":"10.1139","volume":"99","author":[{"given":"Junko","family":"Tachi","sequence":"first","affiliation":[{"name":"Department of Anesthesiology and Pain Medicine, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan."},{"name":"Department of Pharmacology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takashi","family":"Onuma","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Pain Medicine, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shinobu","family":"Yamaguchi","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Pain Medicine, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Woo","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Pain Medicine, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan."},{"name":"Department of Pharmacology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tomoyuki","family":"Hioki","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan."},{"name":"Department of Dermatology, Kizawa Memorial Hospital, Minokamo 505-8503, Japan."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rie","family":"Matsushima-Nishiwaki","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kumiko","family":"Tanabe","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Pain Medicine, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haruhiko","family":"Tokuda","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan."},{"name":"Department of Clinical Laboratory\/Medical Genome Center Biobank, National Center for Geriatrics and Gerontology, Obu 474-8511, Japan."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Osamu","family":"Kozawa","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hiroki","family":"Iida","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Pain Medicine, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan."}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"155","reference":[{"key":"refg1\/ref1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1204929109"},{"key":"refg2\/ref2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijom.2017.03.034"},{"key":"refg3\/ref3","doi-asserted-by":"publisher","DOI":"10.1002\/jbmr.3045"},{"key":"refg4\/ref4","doi-asserted-by":"publisher","DOI":"10.1016\/j.febslet.2012.04.030"},{"key":"refg5\/ref5","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.1977.tb07528.x"},{"key":"refg6\/ref6","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2015.04.029"},{"key":"refg7\/ref7","doi-asserted-by":"publisher","DOI":"10.1016\/j.biocel.2010.09.018"},{"key":"refg8\/ref8","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2019.108853"},{"key":"refg9\/ref9","doi-asserted-by":"publisher","DOI":"10.3892\/etm.2017.4491"},{"key":"refg10\/ref10","doi-asserted-by":"publisher","DOI":"10.1155\/2014\/798060"},{"key":"refg11\/ref11","doi-asserted-by":"publisher","DOI":"10.1002\/jcb.20734"},{"key":"refg12\/ref12","doi-asserted-by":"publisher","DOI":"10.1016\/j.bone.2009.07.083"},{"key":"refg13\/ref13","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2010.04.078"},{"key":"refg14\/ref14","first-page":"268","volume":"4","author":"Hofbauer L.C.","year":"2004","journal-title":"J. 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