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dc.contributor.authorWang, H.
dc.contributor.authorJia, Tanghong
dc.contributor.authorZacharias, Nora M.
dc.contributor.authorGong, Weiming
dc.contributor.authorDu, Hongxia
dc.contributor.authorWooley, Paul H.
dc.contributor.authorYang, Shang-You
dc.identifier.citationH Wang, T-H Jia, N Zacharias, W Gong, H-X Du, P H Wooley, S-Y Yang; Combination gene therapy targeting on interleukin-1[beta] and RANKL for wear debris-induced aseptic loosening; Gene Ther Feb.2013, V.20, No.2; P128-135en_US
dc.identifier.issn1476-5462 (Electronic)
dc.identifier.issn0969-7128 (Linking)
dc.descriptionClick on the DOI link to access this article (may not be free)en_US
dc.description.abstractThis study investigated the efficacy of a combination gene therapy to repress interleukin-1 (IL-1) and receptor activator of nuclear factor NF-kappa B ligand (RANKL) for the treatment of particulate debris-induced aseptic loosening, and tried to explore the molecular mechanism of the exogenous gene modifications on osteoclastogenesis. RAW cells activated by titanium particles were transduced with DFG-IL-1Ra (retroviral vector encoding IL-1 receptor antagonist) and AAV-OPG (adeno-associated viral vectors—osteoprotegerin) individually or in combination for 4 weeks. Pro-inflammatory cytokines in culture media were determined by enzyme-linked immunosorbent assay, and gene expressions of RANK, IL-1β, c-Fos, TRAF6, JNK1 and CPK were examined using real-time PCR. An established knee-implant-failure mouse model was employed to evaluate the efficacy of the in vivo double-gene therapy. The surgical implantation of a titanium alloy pin into the proximal tibia was followed by monthly challenge with titanium debris. Peri-implant gene transfers of IL-1Ra and OPG (respectively or in combination) were given 3 weeks after surgery. The combination of OPG and IL-1Ra gene transfer exhibited strong synergetic effects in blockage of inflammation and osteoclastogenesis at 8 weeks after gene modification. The combination therapy reversed peri-implant bone resorption and restored implant stability when compared with either single gene transduction. Real-time PCR data indicated that the action of IL-1Ra gene therapy may be mediated via the JNK1 pathway, while the reduction of osteoclastogenesis by OPG gene modification may be regulated by c-Fos expression. In addition, both gene modifications resulted in significant diminishment of TRAF6 expression.en_US
dc.publisherMacmillan Publishers Limiteden_US
dc.relation.ispartofseriesGene Therapy;
dc.relation.ispartofseries;V.20, No.2
dc.titleCombination gene therapy targeting on interleukin-1β and RANKL for wear debris-induced aseptic looseningen_US
dc.description.versionPeer reviewed
dc.rights.holderCopyright © 2013, Rights Managed by Nature Publishing Group

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