Fluoxetine induces direct inhibitory effects on mesenchymal stem cell‑derived osteoprogenitor cells independent of serotonin concentration

Koura,Samar  M.; Salama,Mohamed; El‑Hussiny,Mahmoud; Khalil,Mahmoud  El‑Sayed Awad; Lotfy,Ahmed; Hassan,Samia  Ahmed; Gad Elhak,Seham  Aly; Sobh,Mohamed  A.

doi:10.3892/mmr.2019.9924

Fluoxetine induces direct inhibitory effects on mesenchymal stem cell‑derived osteoprogenitor cells independent of serotonin concentration

Authors:
- Samar M. Koura
- Mohamed Salama
- Mahmoud El‑Hussiny
- Mahmoud El‑Sayed Awad Khalil
- Ahmed Lotfy
- Samia Ahmed Hassan
- Seham Aly Gad Elhak
- Mohamed A. Sobh
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Affiliations: Forensic Medicine and Clinical Toxicology Department, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt, Medical Experimental Research Center, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt, Biotechnology and Life Sciences Department, Faculty of Postgraduate Studies for Advanced Sciences, Beni Suef University, Beni Suef 62511, Egypt, Urology and Nephrology Center, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt
Published online on: February 1, 2019 https://doi.org/10.3892/mmr.2019.9924
Pages: 2611-2619
Copyright: © Koura et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Selective serotonin reuptake inhibitors are the most commonly prescribed antidepressants worldwide, which have been reported to exert potential detrimental effects on bone mineral density and increase the risk of developing fractures. The present study aimed to investigate the pathways underlying the negative effects of fluoxetine on bone using mesenchymal stem cells (MSCs) derived from rat adipose tissue as a source of osteoprogenitor cells. MSCs were harvested from adipose tissue using a collagenase enzyme digestion method and were allowed to differentiate into osteoprogenitor cells. Various concentrations of fluoxetine were added to the cells, which were harvested and analyzed by flow cytometry to detect apoptotic markers Annexin V and caspase‑3, in order to assess the levels of apoptosis. The levels of endogenous serotonin released in the extracellular matrix were measured using a serotonin ELISA kit. The underlying molecular pathways associated with the effects of fluoxetine on bone were investigated with reverse transcription‑quantitative polymerase chain reaction. The results of the present study revealed a significant dose‑dependent increase in apoptosis in response to increasing doses of fluoxetine, which was independent of serotonin levels in the culture supernatant. These findings indicated that fluoxetine exerted a direct inhibitory effect on bone cells via an apoptosis‑dependent pathway. Furthermore, the expression levels of serotonergic genes, including serotonin 1B receptor, serotonin 2A receptor (HTR2A), serotonin 2B receptor and serotonin transporter, were down regulated; of these genes, HTR2A exhibited the highest expression levels. Further in vitro and in vivo studies are required to verify this association and to determine the molecular pathways involved in fluoxetine‑induced bone loss. Fluoxetine‑induced apoptosis of osteoprogenitor cells may be the mechanism underlying the increased incidence of bone loss observed in patients treated with fluoxetine.

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