title: TCF3, a novel positive regulator of osteogenesis, plays a crucial role in miR-17 modulating the diverse effect of canonical Wnt signaling in different microenvironments.
abstract: Wnt signaling pathways are a highly conserved pathway, which plays an important role from the embryonic development to bone formation. The effect of Wnt pathway on osteogenesis relies on their cellular environment and the expression of target genes. However, the molecular mechanism of that remains unclear. On the basis of the preliminary results, we observed the contrary effect of canonical Wnt signaling on osteogenic differentiation of periodontal ligament stem cells (PDLSCs) in the different culture environment. Furthermore, we found that the expression level of miR-17 was also varied with the change in the culture environment. Therefore, we hypothesized that miR-17 and canonical Wnt signaling may have potential interactions, particularly the inner regulation relationship in different microenvironments. In this paper, we observed that canonical Wnt signaling promoted osteogenesis of PDLSCs in the fully culture medium, while inhibited it in the osteogenic differentiation medium. Interestingly, alteration in the expression level of endogenous miR-17 could partially reverse the different effect of canonical Wnt signaling. Furthermore, the role of miR-17 was because of its target gene TCF3 (transcription factor 3), a key transcription factor of canonical Wnt pathway. Overexpression of TCF3 attenuated the effect of miR-17 on modulating canonical Wnt signaling. Finally, we elucidated that TCF3 enhanced osteogenesis both in vitro and in vivo. In brief, the different level of miR-17 was the main cause of the different effect of canonical Wnt signaling, and TCF3 was the crucial node of miR-17-canonial Wnt signaling regulation loop. This understanding of microRNAs regulating signaling pathways in different microenvironments may pave the way for fine-tuning the process of osteogenesis in bone-related disorders.
authors.affiliation: Department of Orthodontics, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, People's Republic of China.
authors.forename: W
authors.initials: W
authors.lastname: Liu
authors.forename: Y
authors.initials: Y
authors.lastname: Liu
authors.forename: T
authors.initials: T
authors.lastname: Guo
authors.forename: C
authors.initials: C
authors.lastname: Hu
authors.forename: H
authors.initials: H
authors.lastname: Luo
authors.forename: L
authors.initials: L
authors.lastname: Zhang
authors.forename: S
authors.initials: S
authors.lastname: Shi
authors.forename: T
authors.initials: T
authors.lastname: Cai
authors.forename: Y
authors.initials: Y
authors.lastname: Ding
authors.forename: Y
authors.initials: Y
authors.lastname: Jin
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics* / Q000378:metabolism; D002454:Cell Differentiation; D002478:Cells, Cultured; D060833:Cellular Microenvironment; D005786:Gene Expression Regulation; D006801:Humans; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D016513:Mice, SCID; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism*; D010012:Osteogenesis / Q000235:genetics*; D010513:Periodontal Ligament / Q000166:cytology / Q000378:metabolism; D015398:Signal Transduction; D051153:Wnt Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D035683:MicroRNAs; D051153:Wnt Proteins; C524941:MIRN17 microRNA, human; C407909:TCF3 protein, human