Research Paper Volume 11, Issue 24 pp 12476—12496
lncRNA Rmst acts as an important mediator of BMP9-induced osteogenic differentiation of mesenchymal stem cells (MSCs) by antagonizing Notch-targeting microRNAs
- 1 Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- 2 Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
- 3 Ministry of Education Key Laboratory of Diagnostic Medicine and the School of Laboratory Medicine; and the Affiliated Hospitals of Chongqing Medical University, Chongqing 400016, China
- 4 Key Laboratory of Orthopaedic Surgery of Gansu Province, and the Departments of Orthopaedic Surgery and Obstetrics and Gynecology, The First and Second Hospitals of Lanzhou University, Lanzhou 730030, China
- 5 Department of General Surgery, The Second Affiliated Hospital of Soochow University, Suzhou 215004, China
- 6 Departments of Orthopaedic Surgery and Laboratory Medicine, Chongqing General Hospital, Chongqing 400013, China
- 7 School of Life Sciences, Southwest University, Chongqing 400715, China
- 8 Department of Burn and Plastic Surgery, West China Hospital of Sichuan University, Chengdu 610041, China
- 9 Department of Orthopaedic Surgery, The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou 510405, China
- 10 Department of Orthopaedic Surgery, The Affiliated Zhongnan Hospital of Wuhan University, Wuhan 430072, China
- 11 Department of Orthopaedic Surgery, BenQ Medical Center Affiliated with Nanjing Medical University, Nanjing 210000, China
- 12 Department of Orthopaedic Surgery, The Affiliated Hospital of Qingdao University, Qingdao 266061, China
Received: August 29, 2019 Accepted: November 26, 2019 Published: December 11, 2019
https://doi.org/10.18632/aging.102583How to Cite
Copyright © 2019 Zhang et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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.