MicroRNA-378 Suppressed Osteogenesis of MSCs and Impaired Bone Formation via Inactivating Wnt/β-Catenin Signaling

Lu Feng; Jin-Fang Zhang; Liu Shi; Zheng-Meng Yang; Tian-Yi Wu; Hai-Xing Wang; Wei-Ping Lin; Ying-Fei Lu; Jessica Hiu Tung Lo; Da-Hai Zhu; Gang Li

doi:10.1016/j.omtn.2020.07.018

MicroRNA-378 Suppressed Osteogenesis of MSCs and Impaired Bone Formation via Inactivating Wnt/β-Catenin Signaling

Mol Ther Nucleic Acids. 2020 Sep 4:21:1017-1028. doi: 10.1016/j.omtn.2020.07.018. Epub 2020 Jul 15.

Authors

Lu Feng¹, Jin-Fang Zhang², Liu Shi³, Zheng-Meng Yang¹, Tian-Yi Wu⁴, Hai-Xing Wang¹, Wei-Ping Lin¹, Ying-Fei Lu⁵, Jessica Hiu Tung Lo¹, Da-Hai Zhu⁶, Gang Li⁷

Affiliations

¹ Department of Orthopaedics & Traumatology, Li Ka Shing Institute of Health Sciences and Lui Che Woo Institute of Innovative Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, P.R. China.
² Department of Orthopaedics & Traumatology, Li Ka Shing Institute of Health Sciences and Lui Che Woo Institute of Innovative Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, P.R. China; Key Laboratory of Orthopaedics and Traumatology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, The First Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, P.R. China; Laboratory of Orthopaedics & Traumatology, Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou, P.R. China.
³ Department of Orthopaedics & Traumatology, Li Ka Shing Institute of Health Sciences and Lui Che Woo Institute of Innovative Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, P.R. China; Trauma Center, Zhongda Hospital, School of Medicine, Southeast University, No. 87 Ding Jia Qiao, Nanjing, P.R. China; School of Medicine, Southeast University, No. 87 Ding Jia Qiao, Nanjing, P.R. China.
⁴ Department of Orthopaedics & Traumatology, Li Ka Shing Institute of Health Sciences and Lui Che Woo Institute of Innovative Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, P.R. China; Department of Orthopaedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, P.R. China.
⁵ Department of Orthopaedics & Traumatology, Li Ka Shing Institute of Health Sciences and Lui Che Woo Institute of Innovative Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, P.R. China; Central Laboratory, The Affiliated Jiangning Hospital with Nanjing Medical University, Nanjing, Jiangsu 211100, P.R. China.
⁶ The State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, Beijing, P.R. China.
⁷ Department of Orthopaedics & Traumatology, Li Ka Shing Institute of Health Sciences and Lui Che Woo Institute of Innovative Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, P.R. China; The CUHK-ACC Space Medicine Centre on Health Maintenance of Musculoskeletal System, The Chinese University of Hong Kong Shenzhen Research Institute, Shenzhen, P.R. China. Electronic address: gangli@cuhk.edu.hk.

Abstract

MicroRNAs (miRNAs) have been reported to serve as silencers to repress gene expression at post-transcriptional levels. Multiple miRNAs have been demonstrated to play important roles in osteogenesis. MicroRNA (miR)-378, a conserved miRNA, was reported to mediate bone metabolism and influence bone development, but the detailed function and underlying mechanism remain obscure. In this study, the miR-378 transgenic (TG) mouse was developed to study the role of miR-378 in osteogenic differentiation as well as bone formation. The abnormal bone tissues and impaired bone quality were displayed in the miR-378 TG mice, and a delayed healing effect was observed during bone fracture of the miR-378 TG mice. The osteogenic differentiation of mesenchymal stem cells (MSCs) derived from this TG mouse was also inhibited. We also found that miR-378 mimics suppressed, whereas anti-miR-378 promoted osteogenesis of human MSCs. Two Wnt family members, Wnt6 and Wnt10a, were identified as bona fide targets of miR-378, and their expression was decreased by this miRNA, which eventually induced the inactivation of Wnt/β-catenin signaling. Finally, the short hairpin (sh)-miR-378-modified MSCs were locally injected into the fracture sites in an established mouse fracture model. The results indicated that miR-378 inhibitor therapy could promote bone formation and stimulate the healing process in vivo. In conclusion, miR-378 suppressed osteogenesis and bone formation via inactivating Wnt/β-catenin signaling, suggesting that miR-378 may be a potential therapeutic target for bone diseases.

Keywords: Wnt/β-catenin signaling; bone formation; mesenchymal stem cells; miR-378; osteogenesis.