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

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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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Extracellular matrix mineralization and osteoblast gene expression by human adipose tissue-derived stromal cells.

Brian D Hitt, William O Wilkison, E Paschalis … (2001)

Human adipose tissue represents an abundant reservoir of stromal cells with potential utility for tissue engineering. The current study demonstrates the ability of human adipose tissue-derived stromal cells to display some of the hallmarks of osteoblast differentiation in vitro. Following treatment with ascorbate, beta-glycerophosphate, dexamethasone, and 1,25 dihydroxy vitamin D(3), adipose tissue-derived stromal cells mineralize their extracellular matrix based on detection of calcium phosphate deposits using Alizarin Red and von Kossa histochemical stains. Fourier transform infrared analysis demonstrates the apatitic nature of these crystals. Mineralization is accompanied by increased expression or activity of the osteoblast-associated proteins osteocalcin and alkaline phosphatase. These and other osteoblast-associated gene markers are detected based on polymerase chain reaction. In contrast, the adipocyte gene markers--leptin, lipoprotein lipase, and peroxisome proliferator activated receptor gamma2--are reduced under mineralization conditions, consistent with the reciprocal relationship postulated to exist between adipocytes and osteoblasts. The current work supports the presence of a multipotent stromal cell population within human extramedullary adipose tissue. These findings have potential implications for human bone tissue bioengineering.

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Emerging mechanisms and treatments for depression beyond SSRIs and SNRIs.

Elena Dale, Benny Bang-Andersen, Connie Sánchez (2015)

The monoamine hypothesis has been the prevailing hypothesis of depression over the last several decades. It states that depression is associated with reduced monoamine function. Hence efforts to increase monoamine transmission by inhibiting serotonin (5-HT) and norepinephrine (NE) transporters has been a central theme in depression research since the 1960s. The selective 5-HT reuptake inhibitors (SSRIs) and 5-HT and NE reuptake inhibitors (SNRIs) that have emerged from this line of research are currently first line treatment options for major depressive disorder (MDD). One of the recent trends in antidepressant research has been to refine monoaminergic mechanisms by targeting monoaminergic receptors and additional transporters (e.g. with multimodal drugs and triple re-uptake inhibitors) or by adding atypical antipsychotics to SSRI or SNRI treatment. In addition, several other hypotheses of depression have been brought forward in pre-clinical and clinical research based on biological hallmarks of the disease and efficacy of pharmacological interventions. A central strategy has been to target glutamate receptors (for example, with intravenous infusions of the N-methyl-d-aspartate (NMDA) receptor antagonist ketamine). Other strategies have been based on modulation of cholinergic and γ-aminobutyric acid (GABA)ergic transmission, neuronal plasticity, stress/hypothalamic pituitary adrenal(HPA)-axis, the reward system and neuroinflammation. Here we review the pharmacological profiles of compounds that derived from these strategies and have been recently tested in clinical trials with published results. In addition, we discuss putative treatments for depression that are being investigated at the preclinical level and outline future directions for antidepressant research.

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Association of low bone mineral density with selective serotonin reuptake inhibitor use by older men.

Paul K S Chan, M. Haney, M Bliziotes … (2007)

Selective serotonin reuptake inhibitors (SSRIs) are a widely used class of antidepressants that block the serotonin transporter. Osteoblasts and osteocytes express functional serotonin transporters; serotonin transporter gene disruption in mice results in osteopenia; and SSRI use has been associated with increased risk of hip fracture. To determine whether SSRI use is associated with lower bone mineral density (BMD) in older men and to compare the results for SSRIs with those of other antidepressants, we performed a cross-sectional analysis of data from 5995 men 65 years and older participating in the prospective cohort Osteoporotic Fractures in Men Study. Main outcome measures included medication use; BMD at the femoral neck, greater trochanter, and lumbar spine measured by dual-energy x-ray absorptiometry; and potential covariates. In adjusted analyses, mean BMD among SSRI users (n=160) was 3.9% lower at the total hip and 5.9% lower at the lumbar spine compared with BMD in men reporting no antidepressant use (n=5708 [P=.002 for total hip; P<.001 for lumbar spine]). There was no significant difference among users of trazodone hydrochloride (n=52) or tricyclic antidepressants (n=99) compared with nonusers. Adjusting for variables that could be associated with BMD and/or SSRI use did not significantly alter these results. The observed difference in BMD for SSRIs is similar to that seen with glucocorticoids. In this population of men, BMD was lower among those reporting current SSRI use, but not among users of other antidepressants. Further research is needed to confirm this finding in light of widespread SSRI use and potentially important clinical implications.

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Author and article information

Journal

Journal ID (nlm-ta): Mol Med Rep

Journal ID (iso-abbrev): Mol Med Rep

Title: Molecular Medicine Reports

Publisher: D.A. Spandidos

ISSN (Print): 1791-2997

ISSN (Electronic): 1791-3004

Publication date (Print): April 2019

Publication date (Electronic): 01 February 2019

Publication date PMC-release: 01 February 2019

Volume: 19

Issue: 4

Pages: 2611-2619

Affiliations

[1 ]Forensic Medicine and Clinical Toxicology Department, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt

[2 ]Medical Experimental Research Center, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt

[3 ]Biotechnology and Life Sciences Department, Faculty of Postgraduate Studies for Advanced Sciences, Beni Suef University, Beni Suef 62511, Egypt

[4 ]Urology and Nephrology Center, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt

Author notes

Correspondence to: Dr Mohamed Salama, Medical Experimental Research Center, Faculty of Medicine, Mansoura University, El-Gomhourya Street, Mansoura 35516, Egypt, E-mail: toxicsalama@ 123456hotmail.com

[*]

Contributed equally

Article

Publisher ID: mmr-19-04-2611

DOI: 10.3892/mmr.2019.9924

PMC ID: 6423613

PubMed ID: 30720108

SO-VID: b77d94a5-f15c-4a5e-af7b-8a08a7d9c810

License:

This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

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

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Serotonin and BEYOND

Most cited references 20

Extracellular matrix mineralization and osteoblast gene expression by human adipose tissue-derived stromal cells.

Emerging mechanisms and treatments for depression beyond SSRIs and SNRIs.

Association of low bone mineral density with selective serotonin reuptake inhibitor use by older men.

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