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.

Gut-derived serotonin induced by depression promotes breast cancer bone metastasis through the RUNX2/PTHrP/RANKL pathway in mice

“…One explanation for this is that serotonin has an indirectly regulatory function on osteoblasts by acting on breast cancer. In contrast to a study by Kode et al (35), which showed no effect of serotonin on osteoclast differentiation, our studies in vitro found that circulating serotonin had a positive effect on osteoclast differentiation by acting on breast cancer cells. These striking findings suggest that depression decouples the remodeling process of the bone microenvironment by elevating the level of free serotonin, which results in metastatic bone loss by inhibiting bone formation and promoting bone resorption.…”

Inhibition of leukemia cell engraftment and disease progression in mice by osteoblasts

“…Serotonin was given at concentrations ranging from 25 to 100 mM, doses at which it affects the proliferation of cells expressing serotonin receptors. 37,40,41 Neither of these 2 treatments affected leukemic blast proliferation or survival (supplemental Figure 15). To confirm these observations in vivo, EL4 cells were treated with LP533401 or serotonin and subsequently implanted in mice to monitor leukemia engraftment, as commonly described.…”

“…To test this hypothesis, we treated mice with a compound, LP533401, that in rodents increases osteoblast numbers without affecting osteoclasts. [37][38][39][40] This effect involves inhibition of tryptophan hydroxylase-1 (Tph-1), an enzyme required in gut-derivedserotonin synthesis that suppresses osteoblast numbers.…”

Forkhead box O transcription factors as possible mediators in the development of major depression

“…Moreover, in the peripheral system, serotonin also influences the physiological actions of FoxO, for example, serotonin enhances the proliferation of hepatocellular carcinoma cells through upregulation of FoxO3a (Liang et al, 2013) . Duodenum-derived serotonin is a critical regulator of bone mass during the process of bone formation, and importantly FoxO1 mediates this effect (Kode et al, 2012). High circulating serotonin levels prevent the association of FoxO1 with CREB, resulting in suppressed osteoblast proliferation (Kode et al, 2012).…”

“…Duodenum-derived serotonin is a critical regulator of bone mass during the process of bone formation, and importantly FoxO1 mediates this effect (Kode et al, 2012). High circulating serotonin levels prevent the association of FoxO1 with CREB, resulting in suppressed osteoblast proliferation (Kode et al, 2012). …”