Dataset Information

LncRNA Rmst acts as an important mediator of BMP9-induced osteogenic differentiation of mesenchymal stem cells (MSCs) by antagonizing Notch-targeting microRNAs.

ABSTRACT: Understanding the bone and musculoskeletal system is essential to maintain the health and quality of life of our aging society. Mesenchymal stem cells (MSCs) can undergo self-renewal and differentiate into multiple tissue types including bone. We demonstrated that BMP9 is the most potent osteogenic factors although molecular mechanism underlying BMP9 action is not fully understood. Long noncoding RNAs (lncRNAs) play important regulatory roles in many physiological and/or pathologic processes. Here, we investigated the role of lncRNA Rmst in BMP9-induced osteogenic differentiation of MSCs. We found that Rmst was induced by BMP9 through Smad signaling in MSCs. Rmst knockdown diminished BMP9-induced osteogenic, chondrogenic and adipogenic differentiation in vitro, and attenuated BMP9-induced ectopic bone formation. Silencing Rmst decreased the expression of Notch receptors and ligands. Bioinformatic analysis predicted Rmst could directly bind to eight Notch-targeting miRNAs, six of which were downregulated by BMP9. Silencing Rmst restored the expression of four microRNAs (miRNAs). Furthermore, an activating Notch mutant NICD1 effectively rescued the decreased ALP activity caused by Rmst silencing. Collectively, our results strongly suggest that the Rmst-miRNA-Notch regulatory axis may play an important role in mediating BMP9-induced osteogenic differentiation of MSCs.

SUBMITTER: Zhang Z

PROVIDER: S-EPMC6949095 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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lncRNA Rmst acts as an important mediator of BMP9-induced osteogenic differentiation of mesenchymal stem cells (MSCs) by antagonizing Notch-targeting microRNAs.

Zhang Zhicai Z Liu Jianxiang J Zeng Zongyue Z Fan Jiaming J Huang Shifeng S Zhang Linghuan L Zhang Bo B Wang Xi X Feng Yixiao Y Ye Zhenyu Z Zhao Ling L Cao Daigui D Yang Lijuan L Pakvasa Mikhail M Liu Bin B Wagstaff William W Wu Xiaoxing X Luo Huaxiu H Zhang Jing J Zhang Meng M He Fang F Mao Yukun Y Ding Huimin H Zhang Yongtao Y Niu Changchun C Haydon Rex C RC Luu Hue H HH Lee Michael J MJ Wolf Jennifer Moriatis JM Shao Zengwu Z He Tong-Chuan TC

Aging 20191211 24

Understanding the bone and musculoskeletal system is essential to maintain the health and quality of life of our aging society. Mesenchymal stem cells (MSCs) can undergo self-renewal and differentiate into multiple tissue types including bone. We demonstrated that BMP9 is the most potent osteogenic factors although molecular mechanism underlying BMP9 action is not fully understood. Long noncoding RNAs (lncRNAs) play important regulatory roles in many physiological and/or pathologic processes. He ...[more]

PMID: 31825894

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Project description:Small non-coding microRNAs (miRNAs) have the ability to target and bind to many mRNAs within the cytosol resulting in reduced protein expression and modulation of a number of cellular pathways and networks. In addition to the cytosol, miRNAs have been identified in other cellular compartments and organelles, including the mitochondria. While a few mitochondria-associated miRNAs (mitomiRs) are predicted to be derived from the mitochondrial genome, the majority appear to be transcribed from nuclear DNA and somehow transported into the mitochondria. These findings raise interesting questions about why miRNAs are located in the mitochondria and if they play a role in regulating processes within these organelles. Previously published work from our laboratory showed that miR-181a/b can regulate osteogenesis, in part, by enhancing mitochondrial metabolism. In other published studies, miR-181 paralogs and many other miRNAs have been identified in mitochondrial extracts derived from common cell lines and specific primary cells and tissues. Taken together, we were motivated to identify mitomiR expression profiles during in vitro osteogenesis. Specifically, we obtained RNA from purified mitochondrial extracts of human bone marrow-derived mesenchymal stem/stromal cells (MSCs) and from whole cell extracts of MSCs at day 0 or following osteogenic induction for 3, 7 and 14 days. Utilizing Affymetrix GeneChip™ miRNA 4.0 arrays, mitomiR expression signatures were determined at each time point. Based on the Affymetrix detection above background algorithm, the total number of miRNAs detected in MSC mitochondria extracts was 527 (non-induced MSCs), 627 (day 3 induced), 372 (day 7 induced) and 498 (day 14 induced). In addition, we identified significantly differentially-expressed mitomiRs at day 7 and day 14 of osteogenic induction when compared to day 0 (fold change ≥1.5; adjusted p value <0.05). In general, the most pronounced and highly significant changes in mitomiR expression during osteogenesis were observed at the day 7 time point. Interestingly, most miRNAs found to be differentially-expressed in mitochondria extracts did not show significantly altered expression in whole cell extracts at the same time points during osteoblast differentiation. This array study provides novel information on miRNAs associated with the mitochondria in MSCs during differentiation toward the osteoblast phenotype. These findings will guide future research to identify new miRNA candidates that may function in regulating mitochondrial function and/or bone formation, homeostasis or repair.

Dataset Information

LncRNA Rmst acts as an important mediator of BMP9-induced osteogenic differentiation of mesenchymal stem cells (MSCs) by antagonizing Notch-targeting microRNAs.

Publications

lncRNA Rmst acts as an important mediator of BMP9-induced osteogenic differentiation of mesenchymal stem cells (MSCs) by antagonizing Notch-targeting microRNAs.

Similar Datasets

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