Overexpression of miR‐483‐5p/3p cooperate to inhibit mouse liver fibrosis by suppressing the <scp>TGF</scp>‐β stimulated <scp>HSC</scp>s in transgenic mice

Li, Fuyuan; Ma, Ning; Zhao, Ruiqi; Wu, Guodong; Zhang, Yanfen; Qiao, Yu; Han, Dong; Xu, Ya; Xiang, Ying; Yan, Bin; Jin, Jianfeng; Lv, Guixiang; Wang, Lei; Xu, Chi; Gao, Xu; Luo, Shanshun

doi:10.1111/jcmm.12293

Cited by 55 publications

(49 citation statements)

References 40 publications

(53 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…29 Recent findings suggest that miR-483-5p directly targets Timp2 ( Figure 6A) in other cells. 30 Using a luciferase assay ( Figures 6B and 6C), we confirmed that miR-483-5p directly targets Timp2 in the ATDC5 cell line. Moreover, the amount of Timp2 protein in ATDC5 cells was downregulated by miR-483-5p mimics and upregulated by inhibitor, and no difference in Timp2 mRNA levels was found among these groups ( Figure 6D).…”

Section: Mir-483-5p Targets Timp2 To Stimulate Cartilage Angiogenesissupporting

confidence: 54%

Intra-articular Delivery of Antago-miR-483-5p Inhibits Osteoarthritis by Modulating Matrilin 3 and Tissue Inhibitor of Metalloproteinase 2

et al. 2017

View full text Add to dashboard Cite

MicroRNAs (miRNAs) are emerging as important regulators in osteoarthritis (OA) pathogenesis. In our study, a real-time PCR assay revealed that miR-483-5p was upregulated in articular cartilage from OA patients and experimental OA mice induced by destabilization of the medial meniscus compared to their controls. Overexpression of miR-483-5p by intra-articular injection of lentivirus LV3-miR-483-5p significantly enhanced the severity of experimental OA. Consequently, we synthesized antago-miR-483-5p to silence the endogenous miR-483-5p and delivered it intra-articularly, which revealed that antagomiR-483-5p delayed the progression of experimental OA. To investigate the functional mechanism of miR-483-5p in OA development, we generated doxycycline-inducible miR-483 transgenic (TG483) mice. TG483 mice exhibited significant acceleration and increased severity of OA, and age-related OA occurred with higher incidence and greater severity in TG483 mice compared with their controls. Furthermore, our results revealed miR-483-5p directly targeted to the cartilage matrix protein matrilin 3 (Matn3) and tissue inhibitor of metalloproteinase 2 (Timp2) to stimulate chondrocyte hypertrophy, extracellular matrix degradation, and cartilage angiogenesis, and it consequently initiated and accelerated the development of OA. In conclusion, our findings reveal an miRNA functional pathway important for OA development. Targeting of miR-483-5p by intra-articular injection of antago-miR-483-5p represents an approach that could prevent the onset of OA and delay its progression.

show abstract

Section: Mir-483-5p Targets Timp2 To Stimulate Cartilage Angiogenesissupporting

confidence: 54%

Intra-articular Delivery of Antago-miR-483-5p Inhibits Osteoarthritis by Modulating Matrilin 3 and Tissue Inhibitor of Metalloproteinase 2

et al. 2017

View full text Add to dashboard Cite

show abstract

“…Importantly, the use of antagomirs provided powerful evidence that these miRs contribute functionally to the therapeutic actions of EVN. The identification of miR-483-5p is of particular interest because, through the targeting of platelet-derived growth factor and tissue inhibitor of metalloprotease-2, miR-483-5p and -3p (non-EV) were shown to cooperatively suppress HSC activation or CCl 4 -induced liver fibrosis [40]. While the miR-34 family was reported to promote liver fibrosis [41], our data suggests a suppressive effect on fibrogenesis and activation in HSC and this is supported by its ability to diminish epithelial to mesenchymal transition in the kidney [42].…”

Section: Discussionmentioning

confidence: 99%

Therapeutic effects of serum extracellular vesicles in liver fibrosis

Chen

Kemper

et al. 2018

J of Extracellular Vesicle

View full text Add to dashboard Cite

The lack of approved therapies for hepatic fibrosis seriously limits medical management of patients with chronic liver disease. Since extracellular vesicles (EVs) function as conduits for intercellular molecular transfer, we investigated if EVs from healthy individuals have anti-fibrotic properties. Hepatic fibrogenesis or fibrosis in carbon tetrachloride (CCl4)- or thioacetic acid-induced liver injury models in male or female mice were suppressed by serum EVs from normal mice (EVN) but not from fibrotic mice (EVF). CCl4-treated mice undergoing EVN therapy also exhibited reduced levels of hepatocyte death, inflammatory infiltration, circulating AST/ALT levels and hepatic or circulating pro-inflammatory cytokines. Hepatic histology, liver function tests or circulating proinflammatory cytokine levels were unaltered in control mice receiving EVN. As determined using PKH26-labelled EVN, principal target cells included hepatic stellate cells (HSC; a normally quiescent fibroblastic cell that undergoes injury-induced activation and produces fibrosis during chronic injury) or hepatocytes which showed increased EVN binding after, respectively, activation or exposure to CCl4. In vitro, EVN decreased proliferation and fibrosis-associated molecule expression in activated HSC, while reversing the inhibitory effects of CCl4 or ethanol on hepatocyte proliferation. In mice, microRNA-34c, -151-3p, -483-5p, -532-5p and -687 were more highly expressed in EVN than EVF and mimics of these microRNAs (miRs) individually suppressed fibrogenic gene expression in activated HSC. A role for these miRs in contributing to EVN actions was shown by the ability of their corresponding antagomirs to individually and/or collectively block the therapeutic effects of EVN on activated HSC or injured hepatocytes. Similarly, the activated phenotype of human LX-2 HSC was attenuated by serum EVs from healthy human subjects and contained higher miR-34c, -151-3p, -483-5p or -532-5p than EVs from hepatic fibrosis patients. In conclusion, serum EVs from normal healthy individuals are inherently anti-fibrogenic and anti-fibrotic, and contain microRNAs that have therapeutic actions in activated HSC or injured hepatocytes.Abbreviations: ALT: alanine aminotransferase; AST: aspartate aminotransferase; CCl4: carbon tetrachloride; CCN2: connective tissue growth factor; E: eosin; EGFP: enhanced green fluorescent protein; EVs: extracellular vesicles; EVF: serum EVs from mice with experimental hepatic fibrosis; EVN: serum EVs from normal mice; H: hematoxylin; HSC: hepatic stellate cell; IHC: immunohistochemistry; IL: interleukin; MCP-1: monocyte chemotactic protein-1; miR: microRNA; mRNA: messenger RNA; NTA: nanoparticle tracking analysis; PCNA: proliferating cell nuclear antigen; qRT-PCR: quantitative real-time polymerase chain reaction; SDS-PAGE: sodium dodecyl sulphate – polyacrylamide gel electrophoresis; αSMA: alpha smooth muscle actin; TAA: thioacetic acid; TG: transgenic; TGF-β: transforming growth factor beta; TEM: transmission electron microscopy; TNFα...

show abstract

“…Both PDGF-β and TIMP2 are the direct targets of miR-483. Interestingly, overexpression of miR-483 induced carcinogenesis in mouse liver by suppressing cytokine signaling 3 (Socs3) (113).…”

Section: Mir-483mentioning

confidence: 99%

Delivery and Targeting of miRNAs for Treating Liver Fibrosis

Kumar

Mahato

2014

Pharm Res

View full text Add to dashboard Cite

Liver fibrosis is a pathological condition originating from liver damage that leads to excess accumulation of extracellular matrix (ECM) proteins in the liver. Viral infection, chronic injury, local inflammatory responses and oxidative stress are the major factors contributing to the onset and progression of liver fibrosis. Multiple cell types and various growth factors and inflammatory cytokines are involved in the induction and progression of this disease. Various strategies currently being tried to attenuate liver fibrosis include the inhibition of HSC activation or induction of their apoptosis, reduction of collagen production and deposition, decrease in inflammation, and liver transplantation. Liver fibrosis treatment approaches are mainly based on small drug molecules, antibodies, oligonucleotides (ODNs), siRNA and miRNAs. MicroRNAs (miRNA or miR) are endogenous noncoding RNA of ~22 nucleotides that regulate gene expression at post transcription level. There are several miRNAs having aberrant expressions and play a key role in the pathogenesis of liver fibrosis. Single miRNA can target multiple mRNAs, and we can predict its targets based on seed region pairing, thermodynamic stability of pairing and species conservation. For in vivo delivery, we need some additional chemical modification in their structure, and suitable delivery systems like micelles, liposomes and conjugation with targeting or stabilizing the moiety. Here, we discuss the role of miRNAs in fibrogenesis and current approaches of utilizing these miRNAs for treating liver fibrosis.

show abstract

Overexpression of miR‐483‐5p/3p cooperate to inhibit mouse liver fibrosis by suppressing the TGF‐β stimulated HSCs in transgenic mice

Cited by 55 publications

References 40 publications

Intra-articular Delivery of Antago-miR-483-5p Inhibits Osteoarthritis by Modulating Matrilin 3 and Tissue Inhibitor of Metalloproteinase 2

Intra-articular Delivery of Antago-miR-483-5p Inhibits Osteoarthritis by Modulating Matrilin 3 and Tissue Inhibitor of Metalloproteinase 2

Therapeutic effects of serum extracellular vesicles in liver fibrosis

Delivery and Targeting of miRNAs for Treating Liver Fibrosis

Contact Info

Product

Resources

About