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

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.

MicroRNAs Modulate Signaling Pathways in Osteogenic Differentiation of Mesenchymal Stem Cells

“…Wnt6 and Wnt10a were identified as targets of miR-378. In this study, the use of miR-378 mimics could suppress osteogenesis in hMSCs, whereas anti-miR-378 allowed their osteogenic differentiation, thus confirming that miR-378 inhibited osteogenesis via inactivating Wnt/β-catenin signaling [ 136 ]. Further, miR-154-5p negatively regulates hASC osteogenic differentiation under tensile stress, through the Wnt/PCP pathway by directly targeting Wnt11 [ 137 ].…”

MicroRNA‐181a/b‐1‐encapsulated PEG/PLGA nanofibrous scaffold promotes osteogenesis of human mesenchymal stem cells

“…Several signalling mediators that regulate osteogenesis, including Notch ligands, bone morphogenic protein (BMP), Wnt ligands, hormones and growth factors such as tumour necrosis factor (TNF), transforming growth factor (TGF) and cytokines, can be induced by various microRNAs. Findings from numerous studies on the role of miRs in the process of bone differentiation of mesenchymal stem cells (MSCs) have shown that some of them such as miR‐30b and c, miR‐34c, miR‐205, miR‐217, miR‐137‐3p, miR‐9‐5p and miR‐23a cause a decrease and/or suppression of differentiation efficiency in the MSCs 10‐13 . Some others, such as miR‐148b‐3p, miR‐1297, miR‐21‐5p, miR‐129‐5p, miR‐378‐5p, miR‐2861, miR‐22 and miR‐497‐5p, cause an increase degree of osteogenic differentiation in stem cells 14‐19 …”

Dysregulated miRNAs in bone cells of patients with Gorham‐Stout disease

“…The relevance of miR‐378a‐3p in osteoblast function was also demonstrated by its reduction during osteoblastogenesis and by recently published work of Feng et al revealing its role in the suppression of osteogenesis of MSC 41 . Moreover, miR‐378 impairs bone formation via inactivating Wnt/β‐catenin signaling 41 . Regarding the miR‐615‐3p, Real‐Time PCR expression analysis revealed a slight increase in GSD osteoblasts, but a reduction during control osteoblast differentiation.…”

“…However, the increase of miR‐204‐5p was already documented during murine MC3T3‐E1 osteoblast differentiation 40 . The relevance of miR‐378a‐3p in osteoblast function was also demonstrated by its reduction during osteoblastogenesis and by recently published work of Feng et al revealing its role in the suppression of osteogenesis of MSC 41 . Moreover, miR‐378 impairs bone formation via inactivating Wnt/β‐catenin signaling 41 .…”