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

• Published in: Molecular therapy. Nucleic acids 2020-09, Vol.21, p.1017-1028
• Main Authors: Feng, Lu, Zhang, Jin-fang, Shi, Liu, Yang, Zheng-meng, Wu, Tian-yi, Wang, Hai-xing, Lin, Wei-ping, Lu, Ying-fei, Lo, Jessica Hiu Tung, Zhu, Da-hai, Li, Gang
• Format: Article
• Language: English
• Subjects: bone formation; mesenchymal stem cells; miR-378; osteogenesis; Wnt/β-catenin signaling
• ISSN: 2162-2531; 2162-2531
• DOI: 10.1016/j.omtn.2020.07.018

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. [Display omitted] Feng and his colleagues identified impaired bone development and BMSCs osteogenesis in miR-378 transgenic mice. They characterized that miR-378 isoforms directly repress two Wnt family members’ expression, which leads to deactivation of Wnt/β-catenin signaling during osteogenesis. They also demonstrated the effect of miR-378 inhibitor therapy on promoting bone formation in vivo.