title: MiR-17 modulates osteogenic differentiation through a coherent feed-forward loop in mesenchymal stem cells isolated from periodontal ligaments of patients with periodontitis.
abstract: Chronic inflammatory diseases, such as rheumatoid arthritis and periodontitis, are the most common causes of bone tissue destruction. Recently, human periodontal ligament tissue-derived mesenchymal stem cells (PDLSCs), a population of multipotent stem cells, have been used to reconstruct tissues destroyed by chronic inflammation. However, the impact of the local inflammatory microenvironment on tissue-specific stem cells and the mechanisms controlling the effects of the local inflammatory environment remain poorly understood. In this study, we found that the multidifferentiation potential of mesenchymal stem cells (MSCs) isolated from periodontitis-affected periodontal ligament tissue (P-PDLSCs) was significantly lower than that of MSCs isolated from healthy human periodontal ligament tissue (H-PDLSCs). Inflammation in the microenvironment resulted in an inhibition of miR-17 levels, and a perturbation in the expression of miR-17 partly reversed the differentiation potential of PDLSCs in this microenvironment. Furthermore, inflammation in the microenvironment promoted the expression of Smad ubiquitin regulatory factor one (Smurf1), an important negative regulator of MSC osteogenic differentiation. Western blotting and 3' untranslated regions (3'-UTR) reporter assays confirmed that Smurf1 is a direct target of miR-17 in PDLSCs. Our data demonstrate that excessive inflammatory cytokine levels, miR-17, and Smurf1 were all involved in a coherent feed-forward loop. In this circuit, inflammatory cytokines led to direct activation of Smurf1 and downregulation of miR-17, thereby increasing degradation of Smurf1-mediated osteoblast-specific factors. The elucidation of the molecular mechanisms governing MSC osteogenic differentiation in a chronic inflammatory microenvironment could provide us with a better knowledge of chronic inflammatory disorder and improve stem cell-mediated inflammatory bone disease therapy.
authors: Department of Orthodontics, School of Stomatology, Fourth Military Medical University, Xi'an, Shaanxi, China.
authors: Yali
authors: Y
authors: Liu
authors: Wenjia
authors: W
authors: Liu
authors: Chenghu
authors: C
authors: Hu
authors: Zengfu
authors: Z
authors: Xue
authors: Guang
authors: G
authors: Wang
authors: Bofu
authors: B
authors: Ding
authors: Hailang
authors: H
authors: Luo
authors: Liang
authors: L
authors: Tang
authors: Xiangwei
authors: X
authors: Kong
authors: Xiaoyan
authors: X
authors: Chen
authors: Na
authors: N
authors: Liu
authors: Yin
authors: Y
authors: Ding
authors: Yan
authors: Y
authors: Jin
mesh_terms: D000328:Adult; D015153:Blotting, Western; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology*; D002478:Cells, Cultured; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism*; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D010012:Osteogenesis / Q000235:genetics / Q000502:physiology*; D010513:Periodontal Ligament / Q000166:cytology*; D010518:Periodontitis / Q000473:pathology*; D060888:Real-Time Polymerase Chain Reaction; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism
chemical_list: C524941:MIRN17 microRNA, human; D035683:MicroRNAs; C498342:SMURF1 protein, human; D044767:Ubiquitin-Protein Ligases