title: miR-29 inhibits bleomycin-induced pulmonary fibrosis in mice.
abstract: Loss of microRNA-29 (miR-29) is known to be a mechanism of transforming growth factor-β (TGF-β)-mediated pulmonary fibrosis, but the therapeutic implication of miR-29 for pulmonary fibrosis remains unexplored. The present study investigated whether miR-29 had therapeutic potential for lung disease induced by bleomycin in mice. In addition, the signaling mechanisms that regulated miR-29 expression were investigated in vivo and in vitro. We found that miR-29 was a downstream target gene of Smad3 and negatively regulated by TGF-β/Smad signaling in fibrosis. This was evidenced by the findings that mice or pulmonary fibroblasts null for Smad3 were protected against bleomycin or TGF-β1-induced loss of miR-29 along with fibrosis in vivo and in vitro. Interestingly, overexpression of miR-29 could in turn negatively regulated TGF-β and connective tissue growth factor (CTGF) expression and Smad3 signaling. Therefore, Sleeping Beauty (SB)-mediated miR-29 gene transfer into normal and diseased lung tissues was capable of preventing and treating pulmonary fibrosis including inflammatory macrophage infiltration induced by bleomycin in mice. In conclusion, miR-29 is negatively regulated by TGF-β/Smad3 and has a therapeutic potential for pulmonary fibrosis. SB-mediated miR-29 gene therapy is a non-invasive therapeutic strategy for lung disease associated with fibrosis.
authors.affiliation: Department of Medicine and Therapeutics, and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Xiao
authors.forename: Xiao-Ming
authors.initials: XM
authors.lastname: Meng
authors.forename: Xiao R
authors.initials: XR
authors.lastname: Huang
authors.forename: Arthur Ck
authors.initials: AC
authors.lastname: Chung
authors.forename: Yu-Lin
authors.initials: YL
authors.lastname: Feng
authors.forename: David Sc
authors.initials: DS
authors.lastname: Hui
authors.forename: Cheuk-Man
authors.initials: CM
authors.lastname: Yu
authors.forename: Joseph Jy
authors.initials: JJ
authors.lastname: Sung
authors.forename: Hui Y
authors.initials: HY
authors.lastname: Lan
mesh_terms: D000818:Animals; D001761:Bleomycin; D002478:Cells, Cultured; D004251:DNA Transposable Elements; D004195:Disease Models, Animal; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D015870:Gene Expression; D005786:Gene Expression Regulation / Q000187:drug effects; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000008:administration & dosage / Q000378:metabolism*; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000235:genetics* / Q000517:prevention & control*; D015398:Signal Transduction; D051900:Smad3 Protein / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000378:metabolism / Q000494:pharmacology
chemical_list: D004251:DNA Transposable Elements; C547014:MIRN29 microRNA, mouse; D035683:MicroRNAs; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta; D001761:Bleomycin