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: American Society for Clinical Investigation 01.10.2012
• Subjects: Bones; Cyclic adenosine monophosphate response element-binding protein; Density; Osteoblasts; Physiological aspects; Serotonin; 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 FOX01 is a crucial determinant of the effects of duodenum-derived serotonin on bone formation We identified two key FOX01 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 FOX01 was promoted by a balance between its interaction with CREB and ATF4. However, high circulating serotonin levels prevented the association of FOX01 with CREB, resulting in suppressed osteoblast proliferation. These observations identify FOX01 as the molecular node of an intricate transcriptional machinery that confers the signal of duodenal-derived serotonin to inhibit bone formation.