FOXO1 orchestrates the bone-suppressing function of gut-derived serotonin
FOXO1 orchestrates the bone-suppressing function of gut-derived serotonin
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DOI：
10.1172/jci64906
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发表时间：
2012-10-01
影响因子：
15.9
通讯作者：
Kousteni, Stavroula
中科院分区：
文献类型：
--
作者：
Kode, Aruna;Mosialou, Ioanna;Kousteni, Stavroula
血清素是骨量的关键调节剂，根据其合成部位实现不同的功能。脑源性5-羟色胺促进成骨细胞增殖，而脑源性5-羟色胺抑制它。为了了解脑源性5-羟色胺作用于成骨细胞的分子机制，我们探索了其在小鼠中的转录介导。我们发现转录因子FOXO 1是骨形成中骨源性5-羟色胺作用的关键决定因素。我们在成骨细胞中鉴定了两种关键的FOXO 1复合物，一种与转录因子cAMP反应元件结合蛋白1（CREB），另一种与激活转录因子4（ATF 4）。在循环5-羟色胺正常水平下，FOXO 1的增殖活性通过其与CREB和ATF 4的相互作用之间的平衡来促进。然而，高循环5-羟色胺水平阻止FOXO 1与CREB的关联，导致成骨细胞增殖受到抑制。这些观察结果确定FOXO 1作为一个复杂的转录机制的分子节点，赋予神经源性5-羟色胺的信号，以抑制骨形成。
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.