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. ß

ACL Research Retreat VII: An Update on Anterior Cruciate Ligament Injury Risk Factor Identification, Screening, and Prevention

“…207 Even though studies examining the effect of relaxin on collagen metabolism in human knee ligaments in situ are lacking, in vivo and in vitro animal studies and human cell culture studies suggest that relaxin administered at physiologic levels can have a profound effect on soft tissue remodeling. 204,[208][209][210][211] In turn, this may lead to a less organized 212 and less dense (both in fiber diameter and density) collagen structure, 204,212 which may manifest as a weaker and more lax ACL. 186 This concept is supported by an animal model in which guinea pig ACLs treated with relaxin at pregnancy levels were 13% more lax and 36% to 49% weaker.…”

A meta‐analysis to identify novel diagnostic and therapeutic targets for Dupuytren's disease

“…Very recently, Kang et al reported the down‐regulation of collagen synthesis and matrix metalloproteinase expression in myofibroblasts from Dupuytren's nodule using adenovirus‐mediated relaxin gene therapy. Myofibroblastic cells with Ad‐RLN demonstrated a 22% and 48% reduction in collagen I and III mRNA expression, 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 . Dupuytren's contracture is characterized by excessive collagen deposition, which appears as cords causing an extension deficit.…”

“…Myofibroblastic cells with Ad-RLN demonstrated a 22% and 48% reduction in collagen I and III mRNA expression, 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. 24 Dupuytren's contracture is characterized by excessive collagen deposition, which appears as cords causing an extension deficit. In Dupuytren's contracture, there is an increase in the ratio of type III to type I collagen.…”

Prevention of Recurrences in Dupuytren’s Contracture: Are We in the Right Side?

“…Other substances have been postulated for DC treatment and they could be successful under these conditions. Among them, we note, especially, relaxin [36], IGF-II [37], anti-TNFα [38], or imiquimod [39]. Anti-TGFß would be the ideal candidate for the concomitant administration of this preparation.…”