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MiR-483 targets SMAD4 to suppress chondrogenic differentiation of human mesenchymal stem cells.

ABSTRACT: MicroRNAs (miRNAs) can regulate cellular differentiation processes by modulating multiple pathways simultaneously. Previous studies to analyze in vivo miRNA expression patterns in developing human limb cartilage tissue identified significant downregulation of miR-483 in hypertrophic chondrocytes relative to proliferating and differentiated chondrocytes. To test the function of miR-483 during chondrogenesis, lentiviral strategies were used to overexpress miR-483 during in vitro chondrogenesis of human bone marrow-derived mesenchymal stem cells (hBM-MSCs). While the in vivo expression patterns led us to hypothesize that miR-483 may enhance chondrogenesis or suppress hypertrophic marker expression, surprisingly, miR-483 overexpression reduced chondrocyte gene expression and cartilage matrix production. In addition, cell death was induced at later stages of the chondrogenesis assay. Mechanistic studies revealed that miR-483 overexpression resulted in downregulation of the TGF-? pathway member SMAD4, a known direct target of miR-483-3p. From these studies, we conclude that constitutive overexpression of miR-483 in hBM-MSCs inhibits chondrogenesis of these cells and does not represent an effective strategy to attempt to enhance chondrocyte differentiation and anabolism in this system in vitro. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:2369-2377, 2017.

SUBMITTER: Anderson BA

PROVIDER: S-EPMC5573664 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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miR-483 targets SMAD4 to suppress chondrogenic differentiation of human mesenchymal stem cells.

Anderson Britta A BA McAlinden Audrey A

Journal of orthopaedic research : official publication of the Orthopaedic Research Society 20170313 11

MicroRNAs (miRNAs) can regulate cellular differentiation processes by modulating multiple pathways simultaneously. Previous studies to analyze in vivo miRNA expression patterns in developing human limb cartilage tissue identified significant downregulation of miR-483 in hypertrophic chondrocytes relative to proliferating and differentiated chondrocytes. To test the function of miR-483 during chondrogenesis, lentiviral strategies were used to overexpress miR-483 during in vitro chondrogenesis of ...[more]

PMID: 28244607

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Project description:While human mesenchymal stem cells (hMSCs), either in the bone marrow or in tumour microenvironment could be targeted by radiotherapy, their response is poorly understood. The oxic effects on radiosensitivity, cell cycle progression are largely unknown, and the radiation effects on hMSCs differentiation capacities remained unexplored. Here we analysed hMSCs viability and cell cycle progression in 21% O2 and 3% O2 conditions after medical X-rays irradiation. Differentiation towards osteogenesis and chondrogenesis after irradiation was evaluated through an analysis of differentiation specific genes. Finally, a 3D culture model in hypoxia was used to evaluate chondrogenesis in conditions mimicking the natural hMSCs microenvironment. The hMSCs radiosensitivity was not affected by O2 tension. A decreased number of cells in S phase and an increase in G2/M were observed in both O2 tensions after 16 hours but hMSCs released from the G2/M arrest and proliferated at day 7. Osteogenesis was increased after irradiation with an enhancement of mRNA expression of specific osteogenic genes (alkaline phosphatase, osteopontin). Osteoblastic differentiation was altered since matrix deposition was impaired with a decreased expression of collagen I, probably through an increase of its degradation by MMP-3. After induction in monolayers, chondrogenesis was altered after irradiation with an increase in COL1A1 and a decrease in both SOX9 and ACAN mRNA expression. After induction in a 3D culture in hypoxia, chondrogenesis was altered after irradiation with a decrease in COL2A1, ACAN and SOX9 mRNA amounts associated with a RUNX2 increase. Together with collagens I and II proteins decrease, associated to a MMP-13 expression increase, these data show a radiation-induced impairment of chondrogenesis. Finally, a radiation-induced impairment of both osteogenesis and chondrogenesis was characterised by a matrix composition alteration, through inhibition of synthesis and/or increased degradation. Alteration of osteogenesis and chondrogenesis in hMSCs could potentially explain bone/joints defects observed after radiotherapy.

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MiR-483 targets SMAD4 to suppress chondrogenic differentiation of human mesenchymal stem cells.

Publications

miR-483 targets SMAD4 to suppress chondrogenic differentiation of human mesenchymal stem cells.

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