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

Zhicai Zhang^1,², Jianxiang Liu^1,², Zongyue Zeng^2,³, Jiaming Fan^2,³, Shifeng Huang^2,³, Linghuan Zhang^2,³, Bo Zhang^2,⁴, Xi Wang^2,³, Yixiao Feng^2,³, Zhenyu Ye^2,⁵, Ling Zhao^2,³, Daigui Cao^2,^3,⁶, Lijuan Yang^2,⁴, Mikhail Pakvasa², Bin Liu^2,⁷, William Wagstaff², Xiaoxing Wu^2,³, Huaxiu Luo^2,⁸, Jing Zhang^2,³, Meng Zhang^2,⁹, Fang He^2,³, Yukun Mao^2,¹⁰, Huimin Ding^2,¹¹, Yongtao Zhang^2,¹², Changchun Niu^2,⁶, Rex C. Haydon², Hue H. Luu², Michael J. Lee², Jennifer Moriatis Wolf², Zengwu Shao¹, Tong-Chuan He²

¹Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
²Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
³Ministry of Education Key Laboratory of Diagnostic Medicine and the School of Laboratory Medicine; and the Affiliated Hospitals of Chongqing Medical University, Chongqing 400016, China
⁴Key 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
⁵Department of General Surgery, The Second Affiliated Hospital of Soochow University, Suzhou 215004, China
⁶Departments of Orthopaedic Surgery and Laboratory Medicine, Chongqing General Hospital, Chongqing 400013, China
⁷School of Life Sciences, Southwest University, Chongqing 400715, China
⁸Department of Burn and Plastic Surgery, West China Hospital of Sichuan University, Chengdu 610041, China
⁹Department of Orthopaedic Surgery, The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou 510405, China
¹⁰Department of Orthopaedic Surgery, The Affiliated Zhongnan Hospital of Wuhan University, Wuhan 430072, China
¹¹Department of Orthopaedic Surgery, BenQ Medical Center Affiliated with Nanjing Medical University, Nanjing 210000, China
¹²Department of Orthopaedic Surgery, The Affiliated Hospital of Qingdao University, Qingdao 266061, China

Received: August 29, 2019Accepted: November 26, 2019Published: December 11, 2019

https://doi.org/10.18632/aging.102583

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.