title: Therapeutic effect of intra-articular injection of ribbon-type decoy oligonucleotides for hypoxia inducible factor-1 on joint contracture in an immobilized knee animal model.
abstract: BACKGROUND
  Limited range of motion (ROM) as a result of joint contracture in treatment associated with joint immobilization or motor paralysis is a critical issue. However, its molecular mechanism has not been fully clarified and a therapeutic approach is not yet established.
  
  
  METHODS
  In the present study, we investigated its molecular mechanism, focusing on the role of a transcription factor, hypoxia inducible factor-1 (HIF-1), which regulates the expression of connective tissue growth factor (CTGF) and vascular endothelial growth factor (VEGF), and evaluated the possibility of molecular therapy to inhibit HIF-1 activation by ribbon-type decoy oligonucleotides (ODNs) for HIF-1 using immobilized knee animal models.
  
  
  RESULTS
  In a mouse model, ROM of the immobilized knee significantly decreased in a time-dependent manner, accompanied by synovial hypertrophy. Immunohistochemical studies suggested that CTGF and VEGF are implicated in synovial hypertrophy with fibrosis. CTGF and VEGF were up-regulated at both the mRNA and protein levels at 1 and 2 weeks after immobilization, subsequent to up-regulation of HIF-1 mRNA and transcriptional activation of HIF-1. Of importance, intra-articular transfection of decoy ODNs for HIF-1 in a rat model successfully inhibited transcriptional activation of HIF-1, followed by suppression of expression of CTGF and VEGF, resulting in attenuation of restricted ROM, whereas transfection of scrambled decoy ODNs did not.
  
  
  CONCLUSIONS
  The present study demonstrates the important role of HIF-1 in the initial progression of immobilization-induced joint contracture, and indicates the possibility of molecular treatment to prevent the progression of joint contracture prior to intervention with physical therapy. Copyright © 2016 John Wiley & Sons, Ltd.
authors.affiliation: Graduate School of Health Sciences, Morinomiya University of Medical Sciences, Osaka, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Sotobayashi
authors.affiliation: Graduate School of Health Sciences, Morinomiya University of Medical Sciences, Osaka, Japan.
authors.forename: Hirohisa
authors.initials: H
authors.lastname: Kawahata
authors.affiliation: Graduate School of Health Sciences, Morinomiya University of Medical Sciences, Osaka, Japan.
authors.forename: Natsuki
authors.initials: N
authors.lastname: Anada
authors.affiliation: Graduate School of Health Sciences, Morinomiya University of Medical Sciences, Osaka, Japan.
authors.forename: Toshio
authors.initials: T
authors.lastname: Ogihara
authors.affiliation: Department of Clinical Gene Therapy, Graduate School of Medicine, Osaka University, Osaka, Japan.
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Morishita
authors.affiliation: Graduate School of Health Sciences, Morinomiya University of Medical Sciences, Osaka, Japan.
authors.forename: Motokuni
authors.initials: M
authors.lastname: Aoki
mesh_terms: D000818:Animals; D003286:Contracture / Q000235:genetics* / Q000628:therapy; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000037:antagonists & inhibitors / Q000235:genetics*; D007270:Injections, Intra-Articular; D007719:Knee Joint / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008810:Mice, Inbred C57BL; D009841:Oligonucleotides / Q000008:administration & dosage / Q000235:genetics*; D016059:Range of Motion, Articular / Q000235:genetics; D017207:Rats, Sprague-Dawley
chemical_list: D051793:Hypoxia-Inducible Factor 1; D009841:Oligonucleotides
keywords: drug delivery system; gene therapy; hypoxia, hypoxia inducible factor; joint contracture; transcription factor