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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

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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 1

Foxo1 haploinsufficiency rescues the low bone formation phenotype of Lrp5+/– mice.

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Foxo1 haploinsufficiency rescues the low bone formation phenotype of Lr...
(A) Representative vertebral section images from 2-month-old mice. Mineralized bone matrix is stained in black by Von Kossa reagent. Original magnification, ×4. (B) Representative 3D images of transverse CT slices of proximal tibia obtained by high-resolution μCT analysis. (C) Serum serotonin levels (n = 4 mice/group). (D) Osteoblast proliferation as the number of BrdU-stained osteoblasts (Obs) per trabecular area (T.Ar.) or as the percentage of total osteoblasts per trabecular area (n = 6 mice/group) in sections of femurs. (C and D) *P < 0.05 versus WT, #P < 0.05 versus Lrp5+/–Foxo1+/– group. (E and F) Real-Time PCR analysis of indicated genes in bone (n = 6 mice/group). *P < 0.05 versus WT, #P < 0.05 versus Lrp5+/–Foxo1+/– group. (G) Serum serotonin levels (n = 4 mice/group). *P < 0.05 versus WT, #P < 0.05 versus Lrp5–/–Foxo1+/– group. (H) Serum serotonin levels in WT, Lrp5+/–Foxo1+/–, and LP533401-treated Lrp5+/–Foxo1+/– mice. The gut-derived serotonin synthesis inhibitor LP533401 was administered as indicated at 200 mg/kg/d by oral gavage for 4 weeks. Mice were 2 months old (n = 6 mice/group). *P < 0.05 versus WT, #P < 0.05 versus LP533401-treated Lrp5+/–Foxo1+/– group.

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