Upon exposure to fibrotic stress, miR-29b

was down-regulated in stellate cells and hepatocytes, whereas it was up-regulated in Kupffer cells and endothelial cells. Activated hepatic stellate cells are key mediators of fibrosis because they are reported to be the major cell type producing collagen and other ECM proteins in the injured liver. Along with the notion that see more miR-29 directly suppresses the expression of various ECM mRNAs, it has been postulated that miR-29 down-regulation directly leads to the overexpression of ECM gene products during fibrosis. These results also suggest that although miR profiling of RNA isolated from whole organ lysate is useful, the additional effort to obtain samples from purified cell types will provide clearer insights into the molecular pathophysiology. These observations are also consistent with previous studies demonstrating that the increased fibrillar collagen expression in liver fibrosis is primarily posttranscriptional.12 Mechanistically, the authors showed that the treatment of hepatic stellate cells with transforming growth factor β (TGF-β) suppressed miR-29 GDC-0941 in vitro expression; this provided evidence that the fibrogenic effect of TGF-β is mediated in part through the down-regulation of miR-29. TGF-β3 has also been reported to be a direct target of miR-29.13 Such cross-regulatory relationships between miRs and their cognate mRNA targets

are commonly observed. In this case, miR-29 acts as a feed forward switch: the fibrogenic signal initiates TGF-β-induced miR-29 down-regulation. Reduced miR-29

activity further de-represses TGF-β expression and results in amplification of the fibrogenic signal. The miR-29 down-regulation observed during fibrosis directed the authors to investigate its utility as a circulating biomarker for liver fibrosis. Emerging evidence suggests that miRs are found in lipid-enclosed particles in the serum called exosomes.14, 15 During tissue injury, the release of tissue-specific click here miRs (e.g., miR-122 and miR-208 during hepatic and cardiac injuries, respectively) into the circulation has been reported.16, 17 Despite the ubiquitous expression of miR-29 and its modest expression level in the liver among a list of organs tested, this study demonstrated that the amount of circulating miR-29 was significantly inversely correlated with the advancement of fibrotic stages. Altogether, the utility of miR-29 as a circulating biomarker of fibrosis in the liver and other organs warrants further investigation. The repression of ECM genes by miR-29 and its down-regulation during fibrosis strongly suggest that miR-29 down-regulation contributes to the pathogenesis of fibrosis, and the reintroduction of miR-29 could be a novel therapeutic strategy for fibrosis. To test such a hypothesis, one must determine the therapeutic effect of an miR-29 mimic in vivo.