Nature medicine, 2016-10, Vol.22 (10), p.1170-1179
2016
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- Autor(en) / Beteiligte
- Titel
- Serotonin-reuptake inhibitors act centrally to cause bone loss in mice by counteracting a local anti-resorptive effect
- Ist Teil von
- Nature medicine, 2016-10, Vol.22 (10), p.1170-1179
- Ort / Verlag
- New York: Nature Publishing Group US
- Erscheinungsjahr
- 2016
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- Long-term use of serotonin-reuptake inhibitors causes bone loss by acting centrally to counteract a peripheral, beneficial effect on bone. The use of selective serotonin-reuptake inhibitors (SSRIs) has been associated with an increased risk of bone fracture, raising concerns about their increasingly broader usage. This deleterious effect is poorly understood, and thus strategies to avoid this side effect remain elusive. We show here that fluoxetine (Flx), one of the most-prescribed SSRIs, acts on bone remodeling through two distinct mechanisms. Peripherally, Flx has anti-resorptive properties, directly impairing osteoclast differentiation and function through a serotonin-reuptake-independent mechanism that is dependent on intracellular Ca 2+ levels and the transcription factor Nfatc1. With time, however, Flx also triggers a brain-serotonin-dependent rise in sympathetic output that increases bone resorption sufficiently to counteract its local anti-resorptive effect, thus leading to a net effect of impaired bone formation and bone loss. Accordingly, neutralizing this second mode of action through co-treatment with the β-blocker propranolol, while leaving the peripheral effect intact, prevents Flx-induced bone loss in mice. Hence, this study identifies a dual mode of action of SSRIs on bone remodeling and suggests a therapeutic strategy to block the deleterious effect on bone homeostasis from their chronic use.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1078-8956eISSN: 1546-170XDOI: 10.1038/nm.4166Titel-ID: cdi_proquest_journals_2099881222
- Format
- –
- Schlagworte
- 13/1, 13/106, 13/95, 14/63, 38, 38/77, 38/90, 631/378/548/1964, 631/443/63, 631/80/304, 631/92/609, 64/60, 82/1, 82/29, Adrenergic beta-Antagonists - pharmacology, Animals, Antidepressants, Biocompatibility, Biomedical materials, Biomedicine, Bone and Bones - diagnostic imaging, Bone and Bones - drug effects, Bone and Bones - metabolism, Bone growth, Bone loss, Bone remodeling, Bone Remodeling - drug effects, Bone Resorption, Bone turnover, Brain, Calcium (intracellular), Calcium - metabolism, Calcium ions, Cancer Research, Complications and side effects, Fluoxetine, Fluoxetine - pharmacology, Fractures (Injuries), Gene Expression - drug effects, Homeostasis, Immunohistochemistry, In Vitro Techniques, Infectious Diseases, Inhibitors, Metabolic Diseases, Mice, Mice, Knockout, Mode of action, Molecular Medicine, Neurosciences, NFATC Transcription Factors - drug effects, NFATC Transcription Factors - metabolism, Optical Imaging, Osteoclastogenesis, Osteogenesis, Osteogenesis - drug effects, Propranolol, Propranolol - pharmacology, Risk factors, Selective serotonin reuptake inhibitors, Selective Serotonin Reuptake Inhibitors - pharmacology, Serotonin, Serotonin Plasma Membrane Transport Proteins - genetics, Sympathetic Nervous System - drug effects, Tryptophan Hydroxylase - genetics, X-Ray Microtomography