title: Down-regulation of collagen synthesis and matrix metalloproteinase expression in myofibroblasts from Dupuytren nodule using adenovirus-mediated relaxin gene therapy.
abstract: Dupuytren's disease is a fibroproliferative connective tissue disorder characterized by contracture of the palmer fascia of the hand. Relaxin (RLN) is a multifunctional factor which contributes to the remodeling of the pelvic ligament by inhibiting fibrosis and inflammatory activities. The aim of this study was to investigate the effect of the RLN gene on the inhibition of fibrosis in myofibroblastic cells. Myofibroblast cells with adenovirus LacZ (Ad-LacZ) as a marker gene or adenovirus relaxin (Ad-RLN) as therapeutic gene showed transgene expressions in beta-galactosidase assay and Western blot analysis. Myofibroblastic cells with Ad-RLN demonstrated a 22% and 48% reduction in collagen I and III mRNA expressions respectively, a 50% decrease in MMP-1, 70% decrease in MMP-2, 80% decrease in MMP-9, and a 15% reduction in MMP-13 protein expression compared with cultures with viral control and saline control. In addition, myofibroblastic cells with Ad-RLN showed a 40% decrease in TIMP 1 and a 15% increase in TIMP 3 protein expression at 48 h compared to cultures with viral control and saline control. Also, myofibroblastic cell with Ad-RLN demonstrated a 74% inhibition of fibronectin and a 52% decrease in total collagen synthesis at 48 h compared with cultures with viral control and saline control. In conclusion, the RLN gene render antifibrogenic effect on myofibroblastic cells from Dupuytren's nodule via direct inhibition of collagen synthesis not through collagenolytic pathway such as MMP-1, -13, TIMP 1, and 3. Therefore relaxin can be an alternative therapeutic strategy in initial stage of Dupuytren's disease by its antifibrogenic effect.
authors.affiliation: BK21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of, Korea.
authors.forename: Young-Mi
authors.initials: YM
authors.lastname: Kang
authors.forename: Yun-Rak
authors.initials: YR
authors.lastname: Choi
authors.forename: Chae-Ok
authors.initials: CO
authors.lastname: Yun
authors.forename: Jin-Oh
authors.initials: JO
authors.lastname: Park
authors.forename: Kyung-Soo
authors.initials: KS
authors.lastname: Suk
authors.forename: Hak-Sun
authors.initials: HS
authors.lastname: Kim
authors.forename: Moon-Soo
authors.initials: MS
authors.lastname: Park
authors.forename: Byung-Ho
authors.initials: BH
authors.lastname: Lee
authors.forename: Hwan-Mo
authors.initials: HM
authors.lastname: Lee
authors.forename: Seong-Hwan
authors.initials: SH
authors.lastname: Moon
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D002478:Cells, Cultured; D003094:Collagen / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D015536:Down-Regulation / Q000235:genetics; D004387:Dupuytren Contracture / Q000201:enzymology / Q000378:metabolism / Q000628:therapy*; D005353:Fibronectins / Q000378:metabolism; D015316:Genetic Therapy; D006801:Humans; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D058628:Myofibroblasts / Q000378:metabolism*; D012065:Relaxin / Q000235:genetics*; D019714:Tissue Inhibitor of Metalloproteinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D001616:beta-Galactosidase / Q000378:metabolism
chemical_list: D005353:Fibronectins; D019714:Tissue Inhibitor of Metalloproteinases; D012065:Relaxin; D003094:Collagen; D001616:beta-Galactosidase; D020782:Matrix Metalloproteinases
keywords: Dupuytren's disease; collagens; fibrosis; matrix metalloproteinases; relaxin