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.

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.