Abstract
Chondrogenic differentiation of mesenchymal stem cells (MSCs) is accurately regulated by essential transcription factors and signaling cascades. However, the precise mechanisms involved in this process still remain to be defined. MicroRNAs (miRNAs) regulate various biological processes by binding target mRNA to attenuate protein synthesis. To investigate the mechanisms for miRNAs-mediated regulation of chondrogenic differentiation, we identified that miR-145 was decreased during transforming growth factor beta 3 (TGF-β3)-induced chondrogenic differentiation of murine MSCs. Subsequently, dual-luciferase reporter gene assay data demonstrated that miR-145 targets a putative binding site in the 3′-UTR of SRY-related high mobility group-Box gene 9 (Sox9) gene, the key transcription factor for chondrogenesis. In addition, over-expression of miR-145 decreased expression of Sox9 only at protein levels and miR-145 inhibition significantly elevated Sox9 protein levels. Furthermore, over-expression of miR-145 decreased mRNA levels for three chondrogenic marker genes, type II collagen (Col2a1), aggrecan (Agc1), cartilage oligomeric matrix protein (COMP), type IX collagen (Col9a2) and type XI collagen (Col11a1) in C3H10T1/2 cells induced by TGF-β3, whereas anti-miR-145 inhibitor increased the expression of these chondrogenic marker genes. Thus, our studies demonstrated that miR-145 is a key negative regulator of chondrogenic differentiation by directly targeting Sox9 at early stage of chondrogenic differentiation.
Highlights
Bone marrow mesenchymal stem cell (MSCs) possess the potency of self-renewal[1] and multipotential differentiation, such as chondrocytes, osteoblasts, adipocytes[2]
The results confirmed that miR-145 gradually decreased in MSCs, which were induced by transforming growth factor beta 3 (TGF-b3) (Figure 1)
In this study we identified that miR-145 can suppress transforming growth factor (TGF)-b3induced chondrogenic differentiation of MSCs by directly targeting SRYrelated high mobility group-Box gene 9 (Sox9), the key transcription factor for chondrogenesis, at the post-transcriptional level
Summary
Bone marrow mesenchymal stem cell (MSCs) possess the potency of self-renewal[1] and multipotential differentiation, such as chondrocytes, osteoblasts, adipocytes[2]. Chondrogenic differentiation of MSCs is regulated by several transcription factors and growth factors, such as SRYrelated high mobility group-Box (Sox) genes and the transforming growth factor (TGF)-b superfamily, respectively. TGF-b stimulation is necessary for chondrogenesis derived from MSCs[2]. TGF-b3 enhances the early chondrogenesis of MSCs[5] and maintains a chondrogenic phenotype[6]. The cross-talk between TGF-b signal and transcription factors has an important role for the chondrogenesis of MSCs. For example, TGF-b receptorregulated Smad and p300 cooperatively activate the Sox9dependent transcription to promote the early chondrogenesis[7]. Further studies are required to investigate the molecular mechanisms involved in the regulation of chondrogenesis of MSCs in response to the stimulation of TGF-b
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