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Citalopram and Sertraline Exposure Compromises Embryonic Bone Development

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Citalopram and Sertraline Exposure Compromises Embryonic Bone Development Molecular Psychiatry (2016) 21, 656–664 © 2016 Macmillan Publishers Limited All rights reserved 1359-4184/16 www.nature.com/mp ORIGINAL ARTICLE Citalopram and sertraline exposure compromises embryonic bone development D Fraher1,2,6, JM Hodge2,3,6, FM Collier2, JS McMillan3, RL Kennedy3, M Ellis1,2, GC Nicholson3, K Walder1,2, S Dodd2, M Berk2,4, JA Pasco2,5, LJ Williams2,7 and Y Gibert1,2,7 Selective serotonin reuptake inhibitors (SSRIs) are the most commonly prescribed treatments for depression and, as a class of drugs, are among the most used medications in the world. Concern regarding possible effects of SSRI treatment on fetal development has arisen recently as studies have suggested a link between maternal SSRI use and an increase in birth defects such as persistent pulmonary hypertension, seizures and craniosynostosis. Furthermore, SSRI exposure in adults is associated with decreased bone mineral density and increased fracture risk, and serotonin receptors are expressed in human osteoblasts and osteoclasts. To determine possible effects of SSRI exposure on developing bone, we treated both zebrafish, during embryonic development, and human mesenchymal stem cells (MSCs), during differentiation into osteoblasts, with the two most prescribed SSRIs, citalopram and sertraline. SSRI treatment in zebrafish decreased bone mineralization, visualized by alizarin red staining and decreased the expression of mature osteoblast-specific markers during embryogenesis. Furthermore, we showed that this inhibition was not associated with increased apoptosis. In differentiating human MSCs, we observed a decrease in osteoblast activity that was associated with a decrease in expression of the osteoblast-specific genes Runx2, Sparc and Spp1, measured with quantitative real- time PCR (qRT-PCR). Similar to the developing zebrafish, no increase in expression of the apoptotic marker Caspase 3 was observed. Therefore, we propose that SSRIs inhibit bone development by affecting osteoblast maturation during embryonic development and MSC differentiation. These results highlight the need to further investigate the risks of SSRI use during pregnancy in exposing unborn babies to potential skeletal abnormalities. Molecular Psychiatry (2016) 21, 656–664; doi:10.1038/mp.2015.135; published online 8 September 2015 INTRODUCTION women.14 To date, an understanding of the impact of SSRIs on The safety of maternal selective serotonin reuptake inhibitors fetal bone development is lacking. (SSRI) use during pregnancy is of increasing concern with recent The focus of this research, therefore, was to investigate effects studies suggesting associations between SSRIs and increased risk on bone formation during embryonic development following of persistent pulmonary hypertension, low birth weight, preterm exposure to SSRIs. Owing to the ethical and practical limitations of birth, seizures and even infant death.1–4 Decreased birth length studying maternal SSRI use on fetal bone development in humans, fi caused by SSRI use during pregnancy may suggest an effect on our group has used the zebra sh (Danio rerio) as a model to study fi skeletal development.5,6 In adults, SSRI exposure has been shown effects of SSRIs on embryonic bone formation. The zebra sh has been used as a vertebrate model organism for embryogenesis for to increase fracture risk, impair bone metabolism and decrease 15 – over 30 years. The external and rapid development of the bone mineral density.7 10 We recently showed that the human zebrafish makes it an excellent model for developmental biology, bone-forming cells, osteoblasts, and the bone-resorbing cells, – including bone development.16 20 Importantly, regulators of bone osteoclasts, express serotonin receptors and the serotonin formation, cellular organization and bone homeostasis are highly transporter, the target of SSRI action, suggesting a possible fi 21,22 11 conserved between zebra sh and humans. It is also known mechanism for the effect of SSRIs on bone homeostasis. that 84% of human disease-related genes are expressed in Furthermore, SSRIs can accumulate in the bone marrow for zebrafish,23 and these features have allowed us to visualize bone extended periods at concentrations much higher than those 12 formation in vivo following SSRI exposure. To complement our found in blood or the brain. Several SSRIs are currently embryonic in vivo studies, we utilized an in vitro model of human considered as options for use for the treatment of depression 13 osteoblast differentiation from early precursor cells that employs during pregnancy, including citalopram and sertraline. human adipose tissue-derived mesenchymal stem cells (AT-MSCs). Citalopram and sertraline account for ~ 70% of all SSRI prescrip- These multipotent precursor cells provide an excellent source of tions in the United States of America, including for pregnant osteoblast progenitor cells that can differentiate into mature 1Metabolic Genetic Diseases Laboratory, Metabolic Research Unit, School of Medicine, Deakin University, Geelong, VIC, Australia; 2IMPACT and MMR Strategic Research Centres, School of Medicine, Deakin University, Geelong, VIC, Australia; 3Barwon Biomedical Research, University Hospital, Geelong, VIC, Australia; 4Orygen, The National Centre of Excellence in Youth Mental Health and the Centre for Youth Mental Health, Department of Psychiatry, Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC, Australia and 5Department of Medicine, Northwest Academic Centre, The University of Melbourne, St Albans, VIC, Australia. Correspondence: Dr Y Gibert, IMPACT and MMR Strategic Research Centres, School of Medicine, Deakin University, 75 Pidgons Road, Waurn Ponds, Geelong, VIC 3217, Australia. E-mail: [email protected] 6These authors contributed equally to this work. 7These authors are co-senior authors. Received 18 September 2014; revised 15 May 2015; accepted 14 July 2015; published online 8 September 2015 Sertraline and citalopram in bone formation D Fraher et al 657 osteoblasts. To address the knowledge gap regarding the effects of resuspended and filtered through a 100-μm cell strainer to remove SSRI exposure on early bone formation, we have investigated their remaining tissue debris. Cells were pelleted by centrifugation and seeded actions in both an in vivo model of embryogenesis, as well as an at 1 × 106 in tissue culture flasks in basal medium and incubated at 37 °C in fi in vitro human osteoblast model. a humidi ed atmosphere with 5% CO2. Cells were passaged by treatment with 0.025% trypsin/EDTA in phosphate-buffered saline and diluted 1:10 in DMEM/FBS. MSCs were employed in assays after five passages. MATERIALS AND METHODS Ethics statement Differentiation of MSC in medium containing osteogenic factors All zebrafish studies were approved by the Deakin University Animal MSC (104 cells per well) were seeded in 6-mm diameter culture wells in Welfare Committee (81-2011). Human adipose tissue samples were DMEM/FBS and cultured overnight. For MSC differentiation, cells were then obtained with informed, written consent from healthy donors and all cultured in osteogenic medium (DMEM/FBS containing 100 nM dexa- protocols were approved by the Barwon Health Human Research Ethics methasone, 10 mM β-glycerophosphate and 100 mM ascorbate-2-phos- Committee (05–69). phate) in the absence or presence of citalopram or sertraline, and assessed for alkaline phosphatase (ALP) activity. Animal husbandry Zebrafish were reared and staged at 28.5 °C according to Kimmel et al.24 ALP activity assay To determine cellular ALP activity, cells were lysed in 0.1% Triton X-100 for 30 min at room temperature. A pre-warmed solution containing Pharmacological treatment − 10 mg ml 1 p-nitrophenylphosphate in 10% v/v diethanolamine buffer Citalopram (Sigma-Aldrich, St Louis, MO, USA) was stored at − 20 °C in a containing 0.5 mM MgCl2 (pH 9.8) was then added to the lysates and stock concentration of 24.7 mM dissolved in ethanol. Sertraline (Sigma- optical density of samples was assessed using a Tecan Genios Pro − Aldrich) was stored at 20 °C in a stock concentration of 29.2 mM dissolved photospectrometer, at 410 nm at 2.5 min intervals for 30 min. Results were in dimethyl sulphoxide. For treatment, embryos were placed in 50-ml converted to standard international units, equivalent to the conversion by tubes containing 25 ml of E3 embryo medium, supplemented with 0.003% 25 ALP of 1 mM of pNPP to p-nitrophenyl (pNP) per minute. A standard curve phenyl-thiourea to prevent pigmentation. SSRIs were added directly to was generated by serially diluting 1 mM pNP in diethanolamine buffer and the embryonic medium and embryos were allowed to develop in an data presented as relative standard international unit. incubator at 28.5 °C. Measurement of cell viability/apoptosis Bone, cartilage and apoptosis staining Cell viability and apoptosis were assessed by propidium iodide (PI) Alizarin red skeletal staining was performed as previously described by 26 staining and Annexin V (ANV) measurement, respectively. Previously Walker et al. Von Kossa staining was performed as described by Felber untreated MSCs (4 × 105) were freshly prepared and then treated with et al.27 Live embryos were stained for apoptotic cells with the vital dye 28 citalopram or sertraline for 48 h. Cells were dissociated by trypsin digest acridine orange (Sigma-Aldrich) as described by Sassi-Messai et al. (0.025%), recovered for 30 min and then washed in binding buffer Cleaved caspase 3 labeling was performed with BD Pharmigen
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