FOXO1 orchestrates the bone-suppressing function of gut-derived serotonin
Aruna Kode, … , X. Edward Guo, Stavroula Kousteni
Aruna Kode, … , X. Edward Guo, Stavroula Kousteni
Published September 4, 2012
Citation Information: J Clin Invest. 2012;122(10):3490-3503. https://doi.org/10.1172/JCI64906.
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Research Article Bone biology

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

Abstract

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.

Authors

Aruna Kode, Ioanna Mosialou, Barbara C. Silva, Marie-Therese Rached, Bin Zhou, Ji Wang, Tim M. Townes, Rene Hen, Ronald A. DePinho, X. Edward Guo, Stavroula Kousteni

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Figure 2

Serotonin suppresses osteoblast proliferation through FOXO1.

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Serotonin suppresses osteoblast proliferation through FOXO1. (A) SOD2 ac...
(A) SOD2 activity in osteoblasts treated with serotonin (5-HT; 100 μM) for 6 hours (n = 3). *P < 0.05 versus vehicle. (B) Calvaria cells cotransfected with Lrp5 and FOXO-Luc plasmids and treated with vehicle or 100 μM serotonin for 24 hours (n = 3). EV, empty vector. *P < 0.05 versus empty vector, #P < 0.05 versus FOXO-Luc vehicle. (C) Real-time PCR analysis of the expression of Ccnd1 and Ccnd2 in calvaria cells treated with serotonin (100 μM) for 6 hours (n = 3). *P < 0.05 versus vehicle. (D) Calvaria cells from WT and Foxo1ob–/– mice were treated with serotonin (100 μM) for 48 hours, and proliferation was assessed by Cell Titer One (left) or BrdU incorporation (right) (n = 3). *P < 0.05 versus vehicle. (E and F) Calvaria cells from WT and Foxo1ob–/– mice were treated with serotonin (100 μM) for 48 hours. Gene expression of (E) Ccnd1 and (F) Ccnd2 (n = 3). *P < 0.05 versus vehicle. (G) Western blot analysis showing phosphorylation of PKA in WT and Foxo1-deficient osteoblasts treated with serotonin (100 μM) for 30 minutes. (H) Serum serotonin levels (n = 4 mice/group). *P < 0.05 versus WT, #P < 0.05 versus Lrp5+/–Foxo1ob–/– group.