Abstract
Both the miR-17-92 cluster and autophagy have been suggested as critical regulators of bone development, but the potential correlation between the two factors is largely unknown. Hence, we investigated whether members of this cluster can regulate chondrogenesis through an autophagy-related signalling pathway. In this study, the expression of miR-17-92 cluster members and the level of autophagic activity were investigated during chondrogenic induction in ATDC5 cells. miR-17, miR-18a, miR-20a, and miR-92-1 showed significant changes, and the level of autophagic activity was enhanced. Among the miR-17-92 cluster members, miR-20a showed the most significant change. Histological, cellular and molecular analyses were performed after the regulation of miR-20a and autophagy. miR-20a and autophagy had the opposite effect on chondrogenic differentiation, and there was a negative correlation between them. Moreover, the expression of the autophagy regulatory gene Atg7 was inhibited by miR-20a. siRNA was then used to knock down Atg7, and the results further indicated that Atg7 might be a potential target of miR-20a in chondrogenic differentiation. In conclusion, miR-20a is a critical negative regulator of chondrogenic differentiation because it inhibits autophagy via Atg7. Other members of the miR-17-92 cluster may have a similar effect, but this hypothesis requires further investigation.
Highlights
Autophagy is acknowledged to play an important role in development and diseases
Chondrogenic differentiation was enhanced in the miR-20a inhibitor group and was decreased in the groups treated with siAtg[7] as demonstrated by alcian blue and ALP staining (Fig. 6L–O). These data suggest that Atg[7] is a potential target through which miR-20a suppresses autophagy during chondrogenic differentiation. Due to their extensive and rapid proliferation, homogeneity and chondrogenic capacity, ATDC5 cells have been recognized as a good model to study chondrogenesis in vitro
Evidence has shown that ATDC5 cells have properties that replicate the multiple steps of chondrocyte differentiation
Summary
Autophagy is acknowledged to play an important role in development and diseases This process is an evolutionarily conserved intracellular catabolic mechanism that recycles nutrients and energy through the degradation of macromolecules and organelles by lysosomes[1]. By binding to the 3′-UTR of target mRNAs, miRNAs can inhibit protein translation or result in mRNA degradation In this way, they are widely involved in physiological processes such as development, tumourigenesis, cell proliferation and apoptosis[13]. The miR-17-92 cluster is expressed as a polycistronic primary transcript containing six tandem stem-loop hairpins, and it results in six mature miRNAs (miR-17, miR-18a, miR-19a, miR-20a, miR-19b, and miR-92a) This cluster plays pivotal roles in regulating cellular processes, including proliferation, apoptosis, www.nature.com/scientificreports/. Www.nature.com/scientificreports inflammatory activation and autophagy14–18. miR-20a is reported to target Atg[7] and Atg16L and promotes mycobacterial survival in macrophage cells19. miR-18a and miR-92a have been reported to regulate chondrogenesis, but the role of this cluster in chondrogenic differentiation requires further exploration[20,21,22,23]
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