Department of Pharmacodynamics, Medical University of Bialystok, Mickiewicza 2C Str, 15-222 Bialystok, Poland.
Department of Monitored Pharmacotherapy, Medical University of Bialystok, Mickiewicza 2C Str, 15-222 Bialystok, Poland.
Biochim Biophys Acta Mol Basis Dis. 2019 Nov 1;1865(11):165528. doi: 10.1016/j.bbadis.2019.08.004. Epub 2019 Aug 6.
Chronic kidney disease (CKD) is a pathological condition associated with renal osteodystrophy for which there are limited treatment options. Gut-derived serotonin (GDS) is one of the key signaling factors controlling the osteoblast proliferation. Previously, we shown that inhibition of GDS synthesis by LP533401 improved bone mineral status of rats with 5/6 nephrectomy-induced CKD model. Here, we investigated whether the use of LP533401 can modify GDS-dependent molecular pathway involved in osteoblast formation and bone mineralization in CKD rats. The 8-weeks of pharmacological manipulation after a complete CKD development reduced GDS and lead to the advantage of endogenous vitamin D [25(OH)D] over serotonin and parathyroid hormone (PTH) in rats treated with LP533401. The imbalance between GDS - 25(OH)D - PTH resulted in the intensified expression of cAMP- responsive element-binding protein (Creb), whereas the expression of myelocytomatosis oncogene (c-Myc) was simultaneously reduced. This lead to disruption of Foxo1- activating transcription factor 4 (Atf4) complex, and decrease in the expression of the major osteogenic markers. The weakening of excessive osteoblastogenesis was associated with better bone mineral status in all rats with CKD, and especially in LP533401-treated animals. In conclusion, the inhibition of GDS synthesis resulted in the mitigation of osteoblastogenesis observed in CKD, which translated into improvement of bone mineral status. This study provides key mechanistic insights into how modification of GDS-dependent molecular pathway affects bone mineral status in CKD and lays the groundwork for translating the role of functional serotonin signaling in the origin of impaired bone mineral status in patients with CKD.
慢性肾脏病（CKD）是一种与肾性骨营养不良相关的病理状态，其治疗选择有限。肠源性 5-羟色胺（GDS）是控制成骨细胞增殖的关键信号因子之一。此前，我们已经表明，通过 LP533401 抑制 GDS 合成可改善 5/6 肾切除诱导的 CKD 模型大鼠的骨矿物质状态。在这里，我们研究了使用 LP533401 是否可以改变与 CKD 大鼠成骨细胞形成和骨矿化相关的 GDS 依赖性分子途径。在完全 CKD 发展后进行 8 周的药物治疗，降低了 GDS，并使内源性维生素 D[25(OH)D]相对于 5-羟色胺和甲状旁腺激素（PTH）在 LP533401 治疗的大鼠中具有优势。GDS-25(OH)D-PTH 的失衡导致 cAMP 反应元件结合蛋白（Creb）的表达增强，而同时降低了髓样细胞瘤致癌基因（c-Myc）的表达。这导致 Foxo1-激活转录因子 4（Atf4）复合物的破坏，以及主要成骨标志物的表达减少。过多的成骨细胞形成减弱与所有 CKD 大鼠的骨矿物质状态改善有关，尤其是在 LP533401 治疗的动物中。总之，抑制 GDS 合成导致 CKD 中观察到的成骨细胞形成减弱，这转化为骨矿物质状态的改善。这项研究提供了关键的机制见解，说明如何修饰 GDS 依赖性分子途径会影响 CKD 中的骨矿物质状态，并为功能性 5-羟色胺信号在 CKD 患者骨矿物质状态受损中的作用奠定了基础。
