title: Inhibition of the serotonin (5-hydroxytryptamine) transporter reduces bone accrual during growth.
abstract: Selective serotonin-reuptake inhibitors (SSRIs) antagonize the serotonin (5-hydroxytryptamine) transporter (5-HTT), and are frequently prescribed to children and adolescents to treat depression. However, recent findings of functional serotonergic pathways in bone cells and preliminary clinical evidence demonstrating detrimental effects of SSRIs on bone growth have raised questions regarding the effects of these drugs on the growing skeleton. The current work investigated the impact of 5-HTT inhibition on the skeleton in: 1) mice with a null mutation in the gene encoding for the 5-HTT; and 2) growing mice treated with a SSRI. In both models, 5-HTT inhibition had significant detrimental effects on bone mineral accrual. 5-HTT null mutant mice had a consistent skeletal phenotype of reduced mass, altered architecture, and inferior mechanical properties, whereas bone mineral accrual was impaired in growing mice treated with a SSRI. These phenotypes resulted from a reduction in bone formation without an increase in bone resorption and were not influenced by effects on skeletal mechanosensitivity or serum biochemistries. These findings indicate a role for the 5-HTT in the regulation of bone accrual in the growing skeleton and point to a need for further research into the prescription of SSRIs to children and adolescents.
authors.affiliation: Department of Orthopaedic Surgery, Indiana University, 1140 West Michigan Street, CF-326, Indianapolis, Indiana 46202, USA. stwarden@iupui.edu
authors.forename: Stuart J
authors.initials: SJ
authors.lastname: Warden
authors.forename: Alexander G
authors.initials: AG
authors.lastname: Robling
authors.forename: Megan S
authors.initials: MS
authors.lastname: Sanders
authors.forename: Michael M
authors.initials: MM
authors.lastname: Bliziotes
authors.forename: Charles H
authors.initials: CH
authors.lastname: Turner
mesh_terms: D000818:Animals; D015519:Bone Density / Q000187:drug effects / Q000502:physiology*; D001846:Bone Development / Q000187:drug effects / Q000502:physiology*; D005473:Fluoxetine / Q000494:pharmacology; D008465:Mechanoreceptors / Q000502:physiology; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D049990:Membrane Transport Modulators; D026901:Membrane Transport Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D008817:Mice, Mutant Strains; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D013739:Testosterone / Q000097:blood
chemical_list: D005473:Fluoxetine; D008562:Membrane Glycoproteins; D049990:Membrane Transport Modulators; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; D013739:Testosterone; C493231:Slc6a4 protein, mouse