Li Renyao, Dong Ying, Li Feipeng
School of Biological Science and Medical Engineering, Beihang University, Beijing, China.
Naton Biotech (Beijing) Co., Ltd., Beijing, China.
Front Physiol. 2021 Mar 3;12:626248. doi: 10.3389/fphys.2021.626248. eCollection 2021.
ETS proto-oncogene 1 (ETS1) has been implicated in osteoporosis (OP), but the exact molecular mechanisms are complex. This work focuses on the impact of ETS1 on the osteogenic differentiation and the molecules involved. A mouse pre-osteoblast cell line MC3T3-E1 was used for experiments. ETS1 was upregulated during the process of osteogenic differentiation of MC3T3-E1 cells. Overexpression of ETS1 promoted expression of osteogenic markers, alkaline phosphate concentration, and calcareous accumulation in cells. ETS1 was found to specifically bind to miR-128 promoter to suppress its transcription, while miR-128 could target homeobox A13 (HOXA13). Therefore, ETS1 suppressed miR-128 transcription to upregulate HOXA13 expression. Overexpression of HOXA13 promoted the osteogenic differentiation ability of cells and increased the protein level of β-catenin. Either overexpression of miR-128 or downregulation of β-catenin by CWP232228, a β-catenin-specific antagonist, blocked the promoting roles of ETS1 in cells. To conclude, this study provided evidence that ETS1 suppresses miR-128 transcription to activate the following HOXA13/β-catenin axis, therefore promoting osteogenic differentiation ability of MC3T3-E1 cells. This finding may offer novel ideas for OP treatment.
ETS原癌基因1（ETS1）与骨质疏松症（OP）有关，但其确切的分子机制很复杂。这项工作聚焦于ETS1对成骨分化的影响及相关分子。使用小鼠前成骨细胞系MC3T3-E1进行实验。在MC3T3-E1细胞成骨分化过程中ETS1表达上调。ETS1过表达促进了成骨标志物的表达、碱性磷酸酶浓度及细胞内钙质积累。研究发现ETS1特异性结合miR-128启动子以抑制其转录，而miR-128可靶向同源盒A13（HOXA13）。因此，ETS1抑制miR-128转录以上调HOXA13表达。HOXA13过表达促进了细胞的成骨分化能力并增加了β-连环蛋白的蛋白水平。miR-128过表达或使用β-连环蛋白特异性拮抗剂CWP232228下调β-连环蛋白均阻断了ETS1对细胞的促进作用。总之，本研究提供了证据表明ETS1抑制miR-128转录以激活下游的HOXA13/β-连环蛋白轴，从而促进MC3T3-E1细胞的成骨分化能力。这一发现可能为骨质疏松症的治疗提供新思路。
