MicroRNA-146a Regulates Human Foetal Femur Derived Skeletal Stem Cell Differentiation by Down-Regulating SMAD2 and SMAD3

There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

Abstract

MicroRNAs (miRs) play a pivotal role in a variety of biological processes including stem cell differentiation and function. Human foetal femur derived skeletal stem cells (SSCs) display enhanced proliferation and multipotential capacity indicating excellent potential as candidates for tissue engineering applications. This study has examined the expression and role of miRs in human foetal femur derived SSC differentiation along chondrogenic and osteogenic lineages. Cells isolated from the epiphyseal region of the foetal femur expressed higher levels of genes associated with chondrogenesis while cells from the foetal femur diaphyseal region expressed higher levels of genes associated with osteogenic differentiation. In addition to the difference in osteogenic and chondrogenic gene expression, epiphyseal and diaphyseal cells displayed distinct miRs expression profiles. miR-146a was found to be expressed by human foetal femur diaphyseal cells at a significantly enhanced level compared to epiphyseal populations and was predicted to target various components of the TGF-β pathway. Examination of miR-146a function in foetal femur cells confirmed regulation of protein translation of SMAD2 and SMAD3, important TGF-β and activin ligands signal transducers following transient overexpression in epiphyseal cells. The down-regulation of SMAD2 and SMAD3 following overexpression of miR-146a resulted in an up-regulation of the osteogenesis related gene RUNX2 and down-regulation of the chondrogenesis related gene SOX9. The current findings indicate miR-146a plays an important role in skeletogenesis through attenuation of SMAD2 and SMAD3 function and provide further insight into the role of miRs in human skeletal stem cell differentiation modulation with implications therein for bone reparation.

Related collections

Most cited references 34

Record: found
Abstract: found
Article: not found

Wnt/beta-catenin signaling in mesenchymal progenitors controls osteoblast and chondrocyte differentiation during vertebrate skeletogenesis.

Timothy F Day, Xizhi Guo, Lisa Garrett-Beal … (2005)

Chondrocytes and osteoblasts are two primary cell types in the skeletal system that are differentiated from common mesenchymal progenitors. It is believed that osteoblast differentiation is controlled by distinct mechanisms in intramembranous and endochondral ossification. We have found that ectopic canonical Wnt signaling leads to enhanced ossification and suppression of chondrocyte formation. Conversely, genetic inactivation of beta-catenin, an essential component transducing the canonical Wnt signaling, causes ectopic formation of chondrocytes at the expense of osteoblast differentiation during both intramembranous and endochondral ossification. Moreover, inactivation of beta-catenin in mesenchymal progenitor cells in vitro causes chondrocyte differentiation under conditions allowing only osteoblasts to form. Our results demonstrate that beta-catenin is essential in determining whether mesenchymal progenitors will become osteoblasts or chondrocytes regardless of regional locations or ossification mechanisms. Controlling Wnt/beta-catenin signaling is a common molecular mechanism underlying chondrocyte and osteoblast differentiation and specification of intramembranous and endochondral ossification.

0 comments Cited 431 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

MicroRNA control of bone formation and homeostasis.

Jane Lian, Gary Stein, André van Wijnen … (2012)

MicroRNAs (miRNAs) repress cellular protein levels to provide a sophisticated parameter of gene regulation that coordinates a broad spectrum of biological processes. Bone organogenesis is a complex process involving the differentiation and crosstalk of multiple cell types for formation and remodeling of the skeleton. Inhibition of mRNA translation by miRNAs has emerged as an important regulator of developmental osteogenic signaling pathways, osteoblast growth and differentiation, osteoclast-mediated bone resorption activity and bone homeostasis in the adult skeleton. miRNAs control multiple layers of gene regulation for bone development and postnatal functions, from the initial response of stem/progenitor cells to the structural and metabolic activity of the mature tissue. This Review brings into focus an emerging concept of bone-regulating miRNAs, the evidence for which has been gathered largely from in vivo mouse models and in vitro studies in human and mouse skeletal cell populations. Characterization of miRNAs that operate through tissue-specific transcription factors in osteoblast and osteoclast lineage cells, as well as intricate feedforward and reverse loops, has provided novel insights into the supervision of signaling pathways and regulatory networks controlling normal bone formation and turnover. The current knowledge of miRNAs characteristic of human pathologic disorders of the skeleton is presented with a future goal towards translational studies.

0 comments Cited 203 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

The knockout of miR-143 and -145 alters smooth muscle cell maintenance and vascular homeostasis in mice: correlates with human disease

Leonardo Elia, Manuela Quintavalle, Jianlin Zhang … (2009)

Mechanisms controlling vascular smooth muscle cell (VSMC) plasticity and renewal still remain to be completely elucidated. A class of small RNAs called microRNAs (miRs) regulate gene expression at the post-transcriptional level. Here we demonstrate a critical role of the miR-143/145 cluster in SMC differentiation and vascular pathogenesis, also through the generation of a mouse model of miR-143 and -145 knockout. We determined that the expression of miR-143 and -145 is decreased in acute and chronic vascular stress (transverse aortic constriction and in aortas of the ApoE knockout mouse). In human aortic aneurysms, the expression of miR-143 and -145 was significantly decreased compared to control aortas. In addition, overexpression of miR-143 and -145 decreased neointimal formation in a rat model of acute vascular injury. An in-depth analysis of the miR-143/145 knockout mouse model demonstrated that this miR cluster is expressed mostly in the SMC compartment, both during development and post-natally, in vessels and SMC-containing organs. Loss of miR-143 and miR-145 expression induces structural modifications of the aorta, due to an incomplete differentiation of VSMCs. In conclusion, our results demonstrate that the miR-143/145 gene cluster plays a critical role during SMC differentiation and strongly suggest its involvement in the reversion of the VSMC differentiation phenotype that occurs during vascular disease.

0 comments Cited 157 times – based on 0 reviews      Review now

Bookmark

All references

Author and article information

Contributors

Nehad M. Alajez: Role: Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, USA )

ISSN (Electronic): 1932-6203

Publication date Collection: 2014

Publication date (Electronic): 3 June 2014

Volume: 9

Issue: 6

Electronic Location Identifier: e98063

Affiliations

[1 ]Bone and Joint Research Group, Institute of Developmental Sciences, Southampton General Hospital, Southampton, United Kingdom

[2 ]Centre for Human Development, Stem Cells and Regeneration, Human Development and Health, University of Southampton, Southampton, United Kingdom

[3 ]Clinical and Experimental Sciences, University of Southampton, Southampton, United Kingdom

King Saud University, Saudi Arabia

Author notes

* E-mail: richard.oreffo@ 123456soton.ac.uk

Competing Interests: The authors have declared that no competing interests exist.

Conceived and designed the experiments: KSCC ROCO TS. Performed the experiments: KSCC NS PSS. Analyzed the data: KSCC NS PSS TS ROCO. Contributed reagents/materials/analysis tools: DIW TS ROCO. Wrote the paper: KSCC ROCO TS DIW.

Article

Publisher ID: PONE-D-14-08878

DOI: 10.1371/journal.pone.0098063

PMC ID: 4043645

PubMed ID: 24892945

SO-VID: 6c20e59a-d43d-425d-b555-298aef930279

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

History

Date received : 25 February 2014

Date accepted : 27 April 2014

Page count

Pages: 16

Funding

The work carried out in this manuscript was supported by a strategic longer and larger grant (sLOLA) from the Biotechnology and Biological Sciences Research Council UK (BB/G010579/1). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

MicroRNA-146a Regulates Human Foetal Femur Derived Skeletal Stem Cell Differentiation by Down-Regulating SMAD2 and SMAD3

Read this article at

Abstract

Related collections

PLOS Climate

Most cited references 34

Wnt/beta-catenin signaling in mesenchymal progenitors controls osteoblast and chondrocyte differentiation during vertebrate skeletogenesis.

MicroRNA control of bone formation and homeostasis.

The knockout of miR-143 and -145 alters smooth muscle cell maintenance and vascular homeostasis in mice: correlates with human disease

Author and article information

Contributors

Journal

Affiliations

Author notes

Article

History

Page count

Funding

Categories

Comments

Comment on this article

Similar content 434

Cited by 21

Most referenced authors 554