title: Cell-based osteoprotegerin therapy for debris-induced aseptic prosthetic loosening on a murine model.
abstract: Exogenous osteoprotegerin (OPG) gene modification appears a therapeutic strategy for osteolytic aseptic loosening. The feasibility and efficacy of a cell-based OPG gene delivery approach were investigated using a murine model of knee prosthesis failure. A titanium pin was implanted into mouse proximal tibia to mimic a weight-bearing knee arthroplasty, followed by titanium particles challenge to induce periprosthetic osteolysis. Mouse fibroblast-like synoviocytes were transduced in vitro with either AAV-OPG or AAV-LacZ before transfused into the osteolytic prosthetic joint 3 weeks post surgery. Successful transgene expression at the local site was confirmed 4 weeks later after killing. Biomechanical pullout test indicated a significant restoration of implant stability after the cell-based OPG gene therapy. Histology revealed that inflammatory pseudo-membranes existed ubiquitously at bone-implant interface in control groups, whereas only observed sporadically in OPG gene-modified groups. Tartrate-resistant acid phosphatase+osteoclasts and tumor necrosis factor α, interleukin-1β, CD68+ expressing cells were significantly reduced in periprosthetic tissues of OPG gene-modified mice. No transgene dissemination or tumorigenesis was detected in remote organs and tissues. Data suggest that cell-based ex vivo OPG gene therapy was comparable in efficacy with in vivo local gene transfer technique to deliver functional therapeutic OPG activities, effectively halted the debris-induced osteolysis and regained the implant stability in this model.
authors.affiliation: Orthopaedic Research Institute, Via Christi Regional Medical Center, 929 N St Francis Street, Wichita, KS 67214, USA.
authors.forename: L
authors.initials: L
authors.lastname: Zhang
authors.forename: T-H
authors.initials: TH
authors.lastname: Jia
authors.forename: A C M
authors.initials: AC
authors.lastname: Chong
authors.forename: L
authors.initials: L
authors.lastname: Bai
authors.forename: H
authors.initials: H
authors.lastname: Yu
authors.forename: W
authors.initials: W
authors.lastname: Gong
authors.forename: P H
authors.initials: PH
authors.lastname: Wooley
authors.forename: S-Y
authors.initials: SY
authors.lastname: Yang
mesh_terms: D000135:Acid Phosphatase / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors / Q000235:genetics; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D007720:Knee Prosthesis; D051379:Mice; D008807:Mice, Inbred BALB C; D010014:Osteolysis / Q000473:pathology / Q000628:therapy*; D053244:Osteoprotegerin / Q000235:genetics*; D011475:Prosthesis Failure; D000071681:Tartrate-Resistant Acid Phosphatase; D016474:Weight-Bearing; D000097382:CD68 Molecule
chemical_list: D000135:Acid Phosphatase; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D007527:Isoenzymes; D053244:Osteoprotegerin; D000071681:Tartrate-Resistant Acid Phosphatase; C067980:CD68 antigen, human; D000097382:CD68 Molecule