A novel Sprouty4-ERK1/2-Wnt/β-catenin regulatory loop in marrow stromal progenitor cells controls osteogenic and adipogenic differentiation
A novel Sprouty4-ERK1/2-Wnt/β-catenin regulatory loop in marrow stromal progenitor cells controls osteogenic and adipogenic differentiation
复制标题
骨髓基质祖细胞中的新型 Sprouty4-ERK1/2-Wnt/β-连环蛋白调节环控制成骨和脂肪形成分化
DOI：
10.1016/j.metabol.2020.154189
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发表时间：
2020-04-01
影响因子：
9.8
通讯作者：
Wang, Baoli
中科院分区：
文献类型：
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作者：
Tian, Lijie;Xiao, Hongyan;Wang, Baoli
背景：Sprouty(SPRY)蛋白通过抑制受体酪氨酸激酶(RTK)介导的细胞外信号调节激酶(ERK)信号转导，在控制细胞增殖、分化和存活中发挥重要作用。最近的研究表明，SPRY4负向调节血管生成和肿瘤生长。但SPRY4对骨髓间充质干细胞成骨和/或成脂分化的调控作用尚不清楚。结果：在本研究中，我们研究了SPRY4在小鼠骨髓基质前体细胞分化过程中的表达模式，发现其在小鼠骨髓基质前体细胞的分化过程中受到调控，并在去卵巢小鼠干骺端表达增强。体外功能丧失和功能获得研究表明，SPRY4抑制成骨分化，刺激祖细胞成脂分化。体内实验表明，SPRY4在C57BL/6小鼠骨髓中的沉默抑制了去卵巢小鼠的脂肪蓄积，并促进了成骨细胞的分化。机制研究揭示了SPRY4对典型的无翅型MMTV整合位点(WNT)信号和ERK通路的抑制作用。ERK1/2与低密度脂蛋白受体相关蛋白6(LRP6)相互作用，激活规范的Wnt信号通路。Wnt信号失活可减弱SPRY4小干扰RNA对成脂分化的抑制作用和对成骨分化的刺激作用。启动子研究表明，β-catenin在转录水平上抑制了Spry4的表达。结论：我们的研究首次表明，在骨髓基质前体细胞中存在一个新的SPRY4-ERK1/2-Wnt/β-catenin调控环，并在决定细胞命运中起关键作用。它还强调了SPRY4作为治疗骨质疏松症等代谢性骨骼疾病的新治疗靶点的潜力。(C)2020作者。由爱思唯尔公司出版。
Background: Sprouty (SPRY) proteins play critical roles in controlling cell proliferation, differentiation, and survival by inhibiting receptor tyrosine kinase (RTK)-mediated extracellular signal-regulated kinase (ERK) signaling. Recent studies have demonstrated that SPRY4 negatively regulates angiogenesis and tumor growth. However, whether SPRY4 regulates osteogenic and/or adipogenic differentiation of mesenchymal stem cells remains to be explored.Results: In this study, we investigated the expression pattern of Spry4 and found that its expression was regulated during the differentiation of mousemarrow stromal progenitor cells and increased in the metaphysis of ovariectomized mice. In vitro loss-of-function and gain-of-function studies demonstrated that SPRY4 inhibited osteogenic differentiation and stimulated adipogenic differentiation of progenitor cells. In vivo experiments showed that silencing of Spry4 in the marrow of C57BL/6 mice blocked fat accumulation and promoted osteoblast differentiation in ovariectomized mice. Mechanistic investigations revealed the inhibitory effect of SPRY4 on canonical wingless-type MMTV integration site(Wnt) signaling and ERK pathway. ERK1/2 was shown to interact with low-density lipoprotein receptor-related protein 6 (LRP6) and activate the canonical Wnt signaling pathway. Inactivation of Wnt signaling attenuated the inhibition of adipogenic differentiation and stimulation of osteogenic differentiation by Spry4 small interfering RNA (siRNA). Finally, promoter study revealed that beta-catenin transcriptionally inhibited the expression of Spry4.Conclusions: Our study for the first time suggests that a novel SPRY4-ERK1/2-Wnt/beta-catenin regulatory loop exists in marrow stromal progenitor cells and plays a key role in cell fate determination. It also highlights the potential of SPRY4 as a novel therapeutic target for the treatment of metabolic bone disorders such as osteoporosis. (C) 2020 The Authors. Published by Elsevier Inc.