FOXO1 orchestrates the bone-suppressing function of gut-derived serotonin

• Published in: The Journal of clinical investigation Vol. 122; no. 10; pp. 3490 - 3503
• Main Authors: Kode, Aruna, Mosialou, Ioanna, Silva, Barbara C, Rached, Marie-Therese, Zhou, Bin, Wang, Ji, Townes, Tim M, Hen, Rene, DePinho, Ronald A, Guo, X Edward, Kousteni, Stavroula
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01-10-2012
• Subjects: Activating Transcription Factor 4 - physiology; Animals; Biomedical research; Blood-Brain Barrier; Bone Remodeling - physiology; Bones; Cell cycle; Cell Division - drug effects; Cell growth; Cells, Cultured - drug effects; Cyclic adenosine monophosphate response element-binding protein; Cyclic AMP Response Element-Binding Protein - physiology; Density; Duodenum - secretion; Forkhead Box Protein O1; Forkhead Transcription Factors - deficiency; Forkhead Transcription Factors - genetics; Forkhead Transcription Factors - physiology; Gene Expression Regulation; Genes, Reporter; Genotype; Genotype & phenotype; Homeostasis - physiology; Hypotheses; Insulin-Like Growth Factor I - genetics; Low Density Lipoprotein Receptor-Related Protein-5 - deficiency; Low Density Lipoprotein Receptor-Related Protein-5 - genetics; Low Density Lipoprotein Receptor-Related Protein-5 - physiology; MAP Kinase Signaling System - drug effects; Mice; Organ Specificity; Osteoblasts; Osteoblasts - cytology; Osteoblasts - drug effects; Osteoblasts - physiology; Osteogenesis - physiology; Physiological aspects; Promoter Regions, Genetic; Proteins; Receptor, Serotonin, 5-HT1B - deficiency; Receptor, Serotonin, 5-HT1B - genetics; Receptor, Serotonin, 5-HT1B - physiology; Serotonin; Serotonin - blood; Serotonin - pharmacology; Serotonin - physiology; Stress, Physiological - genetics; Transcription factors; Transcription, Genetic; United States
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/jci64906

Serotonin is a critical regulator of bone mass, fulfilling different functions depending on its site of synthesis. Brain-derived serotonin promotes osteoblast proliferation, whereas duodenal-derived serotonin suppresses it. To understand the molecular mechanisms of duodenal-derived serotonin action on osteoblasts, we explored its transcriptional mediation in mice. We found that the transcription factor FOXO1 is a crucial determinant of the effects of duodenum-derived serotonin on bone formation We identified two key FOXO1 complexes in osteoblasts, one with the transcription factor cAMP-responsive element-binding protein 1 (CREB) and another with activating transcription factor 4 (ATF4). Under normal levels of circulating serotonin, the proliferative activity of FOXO1 was promoted by a balance between its interaction with CREB and ATF4. However, high circulating serotonin levels prevented the association of FOXO1 with CREB, resulting in suppressed osteoblast proliferation. These observations identify FOXO1 as the molecular node of an intricate transcriptional machinery that confers the signal of duodenal-derived serotonin to inhibit bone formation.