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      Pulsed Electromagnetic Field Regulates MicroRNA 21 Expression to Activate TGF- β Signaling in Human Bone Marrow Stromal Cells to Enhance Osteoblast Differentiation

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          Abstract

          Pulsed electromagnetic fields (PEMFs) have been documented to promote bone fracture healing in nonunions and increase lumbar spinal fusion rates. However, the molecular mechanisms by which PEMF stimulates differentiation of human bone marrow stromal cells (hBMSCs) into osteoblasts are not well understood. In this study the PEMF effects on hBMSCs were studied by microarray analysis. PEMF stimulation of hBMSCs' cell numbers mainly affected genes of cell cycle regulation, cell structure, and growth receptors or kinase pathways. In the differentiation and mineralization stages, PEMF regulated preosteoblast gene expression and notably, the transforming growth factor-beta (TGF- β) signaling pathway and microRNA 21 (miR21) were most highly regulated. PEMF stimulated activation of Smad2 and miR21-5p expression in differentiated osteoblasts, and TGF- β signaling was essential for PEMF stimulation of alkaline phosphatase mRNA expression. Smad7, an antagonist of the TGF- β signaling pathway, was found to be miR21-5p's putative target gene and PEMF caused a decrease in Smad7 expression. Expression of Runx2 was increased by PEMF treatment and the miR21-5p inhibitor prevented the PEMF stimulation of Runx2 expression in differentiating cells. Thus, PEMF could mediate its effects on bone metabolism by activation of the TGF- β signaling pathway and stimulation of expression of miR21-5p in hBMSCs.

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          TGF-β and BMP Signaling in Osteoblast Differentiation and Bone Formation

          Guiqian Chen, Chuxia Deng, YI-PING LI (2012)
          Transforming growth factor-beta (TGF-β)/bone morphogenic protein (BMP) signaling is involved in a vast majority of cellular processes and is fundamentally important throughout life. TGF-β/BMPs have widely recognized roles in bone formation during mammalian development and exhibit versatile regulatory functions in the body. Signaling transduction by TGF-β/BMPs is specifically through both canonical Smad-dependent pathways (TGF-β/BMP ligands, receptors and Smads) and non-canonical Smad-independent signaling pathway (e.g. p38 mitogen-activated protein kinase pathway, MAPK). Following TGF-β/BMP induction, both the Smad and p38 MAPK pathways converge at the Runx2 gene to control mesenchymal precursor cell differentiation. The coordinated activity of Runx2 and TGF-β/BMP-activated Smads is critical for formation of the skeleton. Recent advances in molecular and genetic studies using gene targeting in mice enable a better understanding of TGF-β/BMP signaling in bone and in the signaling networks underlying osteoblast differentiation and bone formation. This review summarizes the recent advances in our understanding of TGF-β/BMP signaling in bone from studies of genetic mouse models and human diseases caused by the disruption of TGF-β/BMP signaling. This review also highlights the different modes of cross-talk between TGF-β/BMP signaling and the signaling pathways of MAPK, Wnt, Hedgehog, Notch, and FGF in osteoblast differentiation and bone formation.
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            microRNA-21 promotes tumor proliferation and invasion in gastric cancer by targeting PTEN

            Bao-gui Zhang, Jian-fang Li, Bei-qin Yu … (2012)
            Gastric cancer is one of the most common carcinomas in China. microRNAs, a type of non-coding RNA, are important specific regulators and are involved in numerous bioprocesses of an organism. microRNA-21 (miR-21) has been identified as the most suitable choice for further investigation because it is overexpressed in nearly all solid tumors; furthermore, it has been demonstrated that miR-21 is involved in the genesis and progression of human cancer. It has been reported that PTEN, an important tumour suppressor, is regulated by multiple miRNAs. Thus, in this study we focused on the expression and significance of miR-21 in gastric cancer tissues, and the role of miR-21 in the biological behaviour and the expression of PTEN in gastric cancer cells. Real-time PCR was used to detect miR-21 expression in gastric cancer tissues, the adjacent normal tissues, and the gastric cell lines. The gastric cancer cell line BGC-823 was transfected with pre-miR-21/miR-21 inhibitor to overexpress/downregulate miR-21. The influence of miR-21 on the biological behaviour of gastric cancer cells was evaluated using the CCK-8 kit, FCMs, the scratch healing assay and the transwell test. Western blotting and the Luciferase Reporter Assay were used to evaluate the change of PTEN expression after lowered expression of miR-21 in gastric cancer cell lines. Real-time PCR analysis indicated that miR-21 exhibited higher expression in gastric cancer tissues compared to the adjacent non-tumor tissues. miR-21 expression was significantly associated with the degree of differentiation of the tumour tissues (P=0.004), as well as local invasion and lymph node metastasis (P<0.01). After transfection, pre-miR21 BGC-823 cells grew faster than the negative and control groups (P<0.01). The reduction in miR-21 expression demonstrated a remarkable effect on the biological behaviour of gastric cancer cells (P<0.05); the pre-miR-21-transfected cells healed more quickly compared to the control cells in the scratch healing assay, whereas the transwell test indicated that cell migration in vitro was notably inhibited with the downregulation of miR-21 (P<0.05). The western blot results and Luciferase Reporter Assay demonstrated that PTEN expression was remarkably increased after miR-21 inhibition (P<0.05). microRNA-21 expression was upregulated in gastric carcinoma tissues and was significantly associated with the degree of differentiation of tumour tissues, local invasion and lymph node metastasis. Overexpression of miR-21 promoted BGC-823 cell growth, invasion and cell migration in vitro, whereas downregulation of miR-21 exhibited a stronger inhibitory effect on the biological behaviour of gastric cancer cells; additionally, miR-21 inhibition may upregulate the PTEN expression level, which indicates that PTEN may be a target gene for gastric cancer initiation and development.
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              MiR-21 regulates adipogenic differentiation through the modulation of TGF-beta signaling in mesenchymal stem cells derived from human adipose tissue.

              Y. Kim, D. Hwang, Simon Jung … (2009)
              A better understanding of the molecular mechanisms that govern human adipose tissue-derived mesenchymal stem cells (hASCs) differentiation could improve hASCs-based cell therapy and provide new insights into a number of diseases, including obesity. In this study, we examined the roles of microRNA-21 (miR-21) in adipogenic differentiation of hASCs. We found that miR-21 expression was transiently increased after induction of adipogenic differentiation, peaked at 3 days, and returned to the baseline level 8 days. Lentiviral overexpression of miR-21 enhanced adipogenic differentiation. Overexpression of miR-21 decreased both protein and mRNA levels of TGFBR2. The expression of TGFBR2 was decreased during adipogenic differentiation of hASCs in concordance with an increase in the level of miR-21. In contrast, inhibiting miR-21 with 2'-O-methyl-antisense microRNA increased TGFBR2 protein levels in hASCs, accompanied by decreased adipogenic differentiation. The activity of a luciferase construct containing the miR-21 target site from the TGFBR2 3'UTR was lower in LV-miR21-infected hASCs than in LV-miLacZ infected cells. TGF-beta-induced inhibition of adipogenic differentiation was significantly decreased in miR-21 overexpressing cells compared with control lentivirus-transduced cells. RNA interference-mediated downregulation of SMAD3, but not of SMAD2, increased adipogenic differentiation. Overexpression and inhibition of miR-21 altered SMAD3 phosphorylation without affecting total levels of SMAD3 protein. Our data are the first to demonstrate that the role of miR-21 in the adipogenic differentiation of hASCs is mediated through the modulation of TGF-beta signaling. This study improves our knowledge of the molecular mechanisms governing hASCs differentiation, which may underlie the development of obesity or other metabolic diseases.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Stem Cells Int
                Journal ID (iso-abbrev): Stem Cells Int
                Journal ID (publisher-id): SCI
                Title: Stem Cells International
                Publisher: Hindawi
                ISSN (Print): 1687-966X
                ISSN (Electronic): 1687-9678
                Publication date (Print): 2017
                Publication date (Electronic): 23 April 2017
                Volume: 2017
                Electronic Location Identifier: 2450327
                Affiliations
                1Department of Biotechnology, School of Bioengineering, SRM University, Kattankulathur, Tamil Nadu, India
                2Department of Basic Science and Craniofacial Biology, New York University College of Dentistry, New York, NY, USA
                3Department of Cell Biology, New York University School of Medicine, New York, NY, USA
                Author notes
                *Nicola C. Partridge: ncp234@ 123456nyu.edu

                Academic Editor: Elisabetta A. Cavalcanti-Adam

                Author information
                http://orcid.org/0000-0003-3713-1920
                http://orcid.org/0000-0001-5900-7600
                http://orcid.org/0000-0002-5406-4814
                Article
                DOI: 10.1155/2017/2450327
                PMC ID: 5420424
                PubMed ID: 28512472
                SO-VID: 85129fc9-d322-4956-af5d-f58dcc4ee291
                Copyright © Copyright © 2017 Nagarajan Selvamurugan et al.
                License:

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 23 September 2016
                Date revision received : 5 January 2017
                Date accepted : 12 February 2017
                Funding
                Funded by: Orthofix, Inc.
                Categories
                Subject: Research Article

                ScienceOpen disciplines: Molecular medicine
                Data availability:
                ScienceOpen disciplines: Molecular medicine

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