Journal
AGING-US
Volume 11, Issue 24, Pages 12476-12496Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/aging.102583
Keywords
mesenchymal stem cells; BMP9; long noncoding RNAs; IncRNA Rmst; miRNAs
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Funding
- National Key Research and Development Program of China [2016YFC1000803]
- National Institutes of Health [CA226303]
- U.S. Department of Defense [OR130096]
- Chicago Biomedical Consortium
- Searle Funds at The Chicago Community Trust (TCH)
- Scoliosis Research Society
- Medical Scientist Training Program of the National Institutes of Health [T32 GM007281]
- University of Chicago Cancer Center Support Grant [P30CA014599]
- National Center for Advancing Translational Sciences of the National Institutes of Health [UL1 TR000430]
- Mabel Green Myers Research Endowment Fund
- University of Chicago Orthopaedic Surgery Alumni Fund
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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.
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