Mei Yang, Bian Chunjing, Li Jing, Du Zhijian, Zhou Hong, Yang Zhuo, Zhao Robert C H
Center of Excellence in Tissue Engineering, Department of Cell Biology, Institute of Basic Medical Sciences, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China.
J Cell Biochem. 2013 Jun;114(6):1374-84. doi: 10.1002/jcb.24479.
The ERK-MAPK signaling pathway plays a pivotal role during mesenchymal stem cell (MSC) differentiation. Studies have demonstrated that ERK-MAPK promotes adipogenesis and osteogenesis through the phosphorylation of differentiation-associated transcription factors and that it is the only active signaling in all three lineages (adipogenic, chondrogenic, and osteogenic) during MSC differentiation. Recent studies pointed to the significant roles of microRNA-21 (miR-21) during several physiological and pathological processes, especially stem cell fate determination. The miR-21 expression pattern is also correlated with ERK-MAPK activity. Here, we found that miR-21 expression is elevated and associated with an increased differentiation potential in MSCs during adipogenesis and osteogenesis. The overexpression of miR-21 elevated the expression level of the differentiation-associated genes PPARγ and Cbfa-1 during MSC differentiation, whereas miR-21 knockdown reduced the expression level of both genes. The ERK-MAPK signaling pathway activity had an increasing tendency to respond to miR-21 upregulation and a decreasing tendency to respond to miR-21 down-regulation during the first 4 days of adipogenesis and osteogenesis. Our data indicate that miR-21 modulated ERK-MAPK signaling activity by repressing SPRY2 expression, a known regulator of the receptor tyrosine kinase (RTK) signaling pathway, to affect the duration and magnitude of ERK-MAPK activity. The ERK-MAPK signaling pathway was regulated by Sprouty2 (SPRY2) expression via a miR-21-mediated mechanism during MSC differentiation.
ERK-MAPK信号通路在间充质干细胞（MSC）分化过程中起关键作用。研究表明，ERK-MAPK通过分化相关转录因子的磷酸化促进脂肪生成和成骨作用，并且它是MSC分化过程中所有三个谱系（脂肪生成、软骨生成和成骨）中唯一活跃的信号通路。最近的研究指出，微小RNA-21（miR-21）在多个生理和病理过程中发挥重要作用，尤其是在干细胞命运决定方面。miR-21的表达模式也与ERK-MAPK活性相关。在此，我们发现miR-21的表达在MSC脂肪生成和成骨过程中升高，并与分化潜能增加相关。miR-21的过表达在MSC分化过程中提高了分化相关基因PPARγ和Cbfa-1的表达水平，而miR-21敲低则降低了这两个基因的表达水平。在脂肪生成和成骨的前4天，ERK-MAPK信号通路活性对miR-21上调有增加的反应趋势，对miR-21下调有降低的反应趋势。我们的数据表明，miR-21通过抑制SPRY2表达来调节ERK-MAPK信号活性，SPRY2是受体酪氨酸激酶（RTK）信号通路的已知调节因子，从而影响ERK-MAPK活性的持续时间和强度。在MSC分化过程中，ERK-MAPK信号通路通过miR-21介导的机制由Sprouty2（SPRY2）表达调节。
