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A novel Sprouty4-ERK1/2-Wnt/β-catenin regulatory loop in marrow stromal progenitor cells controls osteogenic and adipogenic differentiation.
Metabolism ( IF 9.8 ) Pub Date : 2020-02-24 , DOI: 10.1016/j.metabol.2020.154189
Lijie Tian 1 , Hongyan Xiao 1 , Mengyue Li 1 , Xiaowen Wu 1 , Yan Xie 1 , Jie Zhou 1 , Xin Zhang 1 , Baoli Wang 1
Affiliation  

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 mouse marrow 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 β-catenin transcriptionally inhibited the expression of Spry4. CONCLUSIONS Our study for the first time suggests that a novel SPRY4-ERK1/2-Wnt/β-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.

中文翻译:

骨髓基质祖细胞中的新型Sprouty4-ERK1 / 2-Wnt /β-catenin调节环控制成骨和成脂分化。

背景技术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)信号传导,在控制细胞增殖,分化和存活中起关键作用。最近的研究表明,SPRY4负调节血管生成和肿瘤的生长。然而,SPRY4是否调节间充质干细胞的成骨和/或成脂分化尚待探讨。结果在本研究中,我们调查了Spry4的表达模式,发现其表达在小鼠骨髓基质祖细胞分化过程中受到调控,并在去卵巢小鼠的干physi端中增加。体外功能丧失和功能获得研究表明,SPRY4抑制祖细胞的成骨分化并刺激成脂分化。体内实验表明,C57BL / 6小鼠骨髓中Spry4的沉默可阻断去卵巢小鼠体内的脂肪积累并促进成骨细胞分化。机理研究表明,SPRY4对经典的无翼型MMTV整合位点(Wnt)信号传导和ERK通路具有抑制作用。已显示ERK1 / 2与低密度脂蛋白受体相关蛋白6(LRP6)相互作用并激活经典Wnt信号通路。Wnt信号的失活减弱了Spry4小干扰RNA(siRNA)对成脂分化的抑制和对成骨分化的刺激。最后,启动子研究表明,β-catenin在转录上抑制Spry4的表达。结论我们的研究首次表明,一种新的SPRY4-ERK1 / 2-Wnt /β-catenin调节环存在于骨髓基质祖细胞中,并在确定细胞命运中起关键作用。它还强调了SPRY4作为治疗骨质疏松等代谢性骨疾病的新型治疗靶标的潜力。
更新日期:2020-02-25
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