Department of Orthopedics, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, No.600 Yishan Road, 200233, Xuhui District, Shanghai City, China.
Department of Oncology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, No.600 Yishan Road, 200233, XuhuiDistrict, Shanghai City, China.
Cell Death Dis. 2020 May 15;11(5):372. doi: 10.1038/s41419-020-2572-3.
Osteogenesis (OS) is a type of differentiation that is of great importance for bone homeostasis. Increasing studies suggest circular RNAs (circRNAs) as pivotal regulators in OS. This study proposed to investigate mechanism mediated by circRNAs in OS. Based on GEO data and qRT-PCR assay, we found that circ-DAB1 (has_circ_0113689) was significantly up-regulated during osteogenic differentiation in human BMSCs. Overexpressing circ-DAB1 proliferation and osteogenic differentiation of BMSCs, whereas silencing circ-DAB1 elicited opposite functions. Subsequently, recombination signal-binding protein for immunoglobulin kappa J region (RBPJ), an important transcription factor in NOTCH pathway, was found to interact with DAB1 promoter while not to combine with circ-DAB1. Interestingly, circ-DAB1 overexpression could result in the increasing binding between RBPJ and DAB adaptor protein 1 (DAB1) promoter. Overexpressing circ-DAB1 upregulated RBPJ in BMSCs to induce DAB1 level. Further, we uncovered that circ-DAB1 upregulated RBPJ through sequestering miR-1270 and miR-944. Restoration experiments demonstrated that knocking down either RBPJ or DAB1 partially recovered BMSC proliferation and osteogenic differentiation that was suppressed by circ-DAB1 overexpression. Conclusively, circ-DAB1 promotes cell proliferation and osteogenic differentiation of BMSCs via NOTCH/RBPJ pathway.
成骨作用（OS）是一种对骨骼内稳态非常重要的分化类型。越来越多的研究表明环状 RNA（circRNA）是 OS 中的关键调节因子。本研究旨在探讨 circRNA 在 OS 中介导的机制。基于 GEO 数据和 qRT-PCR 检测，我们发现 circ-DAB1（has_circ_0113689）在人 BMSCs 成骨分化过程中显著上调。过表达 circ-DAB1 可促进 BMSCs 的增殖和成骨分化，而沉默 circ-DAB1 则产生相反的功能。随后，发现信号结合蛋白 J 区（RBPJ），NOTCH 通路中的一个重要转录因子，与 DAB1 启动子相互作用，而不与 circ-DAB1 结合。有趣的是，circ-DAB1 的过表达可导致 RBPJ 与 DAB 衔接蛋白 1（DAB1）启动子的结合增加。过表达 circ-DAB1 可上调 BMSCs 中的 RBPJ，从而诱导 DAB1 水平升高。进一步，我们发现 circ-DAB1 通过隔离 miR-1270 和 miR-944 来上调 RBPJ。恢复实验表明，敲低 RBPJ 或 DAB1 可部分恢复由 circ-DAB1 过表达抑制的 BMSC 增殖和成骨分化。综上所述，circ-DAB1 通过 NOTCH/RBPJ 通路促进 BMSCs 的细胞增殖和成骨分化。
