FOXO3A regulation by miRNA-29a Controls chondrogenic differentiation of mesenchymal stem cells and cartilage formation.
Skeletal development and cartilage formation require stringent regulation of gene expression for mesenchymal stem cells (MSCs) to progress through stages of differentiation. Since microRNAs (miRNAs) regulate biological processes, the objective of the present study was to identify novel miRNAs involved in the modulation of chondrogenesis. We performed miRNA profiling and identify miR-29a as being one of the most down-regulated miRNAs during the chondrogenesis. Using chromatin immunoprecipitation, we showed that SOX9 down-regulates its transcription. Moreover, the over-expression of miR-29a strongly inhibited the expression of chondrocyte-specific markers during in vitro chondrogenic differentiation of MSCs. We identified FOXO3A as a direct target of miR-29a and showed a down- and up-regulation of FOXO3a protein levels after transfection of, respectively, premiR- and antagomiR-29a oligonucleotides. Finally, we showed that using the siRNA or premiR approach, chondrogenic differentiation was inhibited to a similar extent. Together, we demonstrate that the down-regulation of miR-29a, concomitantly with FOXO3A up-regulation, is essential for the differentiation of MSCs into chondrocytes and in vivo cartilage/bone formation. The delivery of miRNAs that modulate MSC chondrogenesis may be applicable for cartilage regeneration and deserves further investigation.
1 Inserm, U 844, Hôpital Saint-Eloi , Montpellier, France .
David
D
Guérit
Jean-Marc
JM
Brondello
Paul
P
Chuchana
Didier
D
Philipot
Karine
K
Toupet
Claire
C
Bony
Christian
C
Jorgensen
Danièle
D
Noël
D000818:Animals; D002356:Cartilage / Q000502:physiology*; D002454:Cell Differentiation / Q000235:genetics; D002478:Cells, Cultured; D019902:Chondrocytes / Q000502:physiology; D020219:Chondrogenesis / Q000235:genetics*; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics*; D005786:Gene Expression Regulation; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000502:physiology*; D051379:Mice; D035683:MicroRNAs / Q000502:physiology*; D010012:Osteogenesis / Q000235:genetics
C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C532045:MIRN29a microRNA, human; D035683:MicroRNAs