MicroRNA-378 suppressed osteogenesis of mesenchymal stem cells and impaired bone formation via inactivating Wnt/β-catenin signaling

Abstract

37MicroRNAs (miRNAs) have been reported to serve as silencers to repress gene 38 expression at post-transcriptional level. Multiple miRNAs have been demonstrated to 39 play important roles in osteogenesis. MiR-378, a conserved miRNA, was reported to 40 mediate bone metabolism and influence bone development, but the detailed function 41 and underlying mechanism remain obscure. In this study, the miR-378 transgenic (TG) 42 mouse was developed to study the role of miR-378 in osteogenic differentiation as 43 well as bone formation. The abnormal bone tissues and impaired bone quality were 44 displayed in the miR-378 TG mice, and a delayed healing effect was observed during 45 bone fracture of the miR-378 TG mice. The osteogenic differentiation of MSCs 46 derived from this TG mouse was also inhibited. We also found that miR-378 mimics 47 suppressed while anti-miR-378 promoted osteogenesis of human MSCs. Two Wnt 48 family members Wnt6 and Wnt10a were identified as bona fide targets of miR-378, 49 and their expression were decreased by this miRNA, which eventually induced the 50 inactivation of Wnt/β-catenin signaling. Finally, the sh-miR-378 modified MSCs were 51 locally injected into the fracture sites in an established mouse fracture model. The 52 results indicated that miR-378 inhibitor therapy could promote bone formation and 53 stimulate healing process in vivo. In conclude, miR-378 suppressed osteogenesis and 54 bone formation via inactivating Wnt/β-catenin signaling, suggesting miR-378 may be 55 a potential therapeutic target for bone diseases.56 Key words: miR-378; mesenchymal stem cells; osteogenesis; Wnt/β-catenin 57 signaling; bone formation 58 59 Bone regeneration is very important for the recovery of some diseases including 60 osteoporosis and bone fracture trauma. It is a multiple step and multiple gene involved 61 complex process, including osteoblast-mediated bone formation and 62 osteoclast-mediated bone resorption. During this process, mesenchymal stem cells 63 (MSCs) gradually differentiate into osteoblasts, which produce a variety of 64 extracellular matrix and thus induce the initiation of bone formation. Hence, 65 improving the osteoblast differentiation of MSCs is crucial for the development of 66 therapeutic strategy for bone diseases. 67 Over the past few years, microRNAs (miRNAs) have emerged as gene silencers to 68 suppress gene expression at post-transcriptional level. Multiple miRNAs have been 69 demonstrated to play important roles in biological activities including osteogenic 70 differentiation and skeletal development. For example, miR-26a, miR-29b, miR-125b, 71 miR-133, miR-135 and miR-196a, have been reported to be involved in 72 osteogenesis. 1-5 Our previous reports also demonstrated that miR-20a and 20b 73 promoted whereas miR-637 suppressed osteoblast differentiation. 6-7 Therefore, 74 miRNAs have been considered as potential candidates to mediate osteogenic 75 differentiation and may be acted as therapeutic targets for bone regeneration.76 MiR-378, which is derived from a ...

Roles of MicroRNAs in Osteogenesis or Adipogenesis Differentiation of Bone Marrow Stromal Progenitor Cells

“…Transfection of microRNA-127 inhibitor enhances osteogenesis in UAM-32 cells as measured by ALP activity and mRNA expression of RUNX2, and transfection of microRNA-136 precursor has inhibitory effects on osteoblastic differentiation, indicating that both microRNA-127 and microRNA-136 negatively regulate osteoblast differentiation [91]. Feng et al found abnormal bone tissues and impaired bone quality in microRNA-378 transgenic mice [92]. It was observed that microRNA-378 suppresses osteogenesis of hBMSCs by targeting Wnt10 and eventually induces the inactivation of Wnt/β-catenin signalling.…”