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Cell-based osteoprotegerin therapy for debris-induced aseptic prosthetic loosening on a murine model.

Zhang L, Jia TH, Chong AC, Bai L, Yu H, Gong W, Wooley PH, Yang SY - Gene Ther. (2010)

Bottom Line: Biomechanical pullout test indicated a significant restoration of implant stability after the cell-based OPG gene therapy.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.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.

View Article: PubMed Central - PubMed

Affiliation: Orthopaedic Research Institute, Via Christi Regional Medical Center, 929 N St Francis Street, Wichita, KS 67214, USA.

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.

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Summary of maximum pulling force required to pull out the implants at 4 weeks following treatments (* p<0.05). The insert illustrates an example trace of pulling forces applied to extract the pin implant from the surrounding bone.
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Figure 2: Summary of maximum pulling force required to pull out the implants at 4 weeks following treatments (* p<0.05). The insert illustrates an example trace of pulling forces applied to extract the pin implant from the surrounding bone.

Mentions: The implanted pin pull-out test was performed to examine the mechanical stability of the implant following wear debris challenge and gene therapy. The average peak interfacial shear strength against pulling was 10.34±2.05, 8.14±1.23 and 7.32±1.35 N in AAV-LacZ, FLS-AAV-LacZ and virus-free non-treated groups respectively. There was no statistical difference between the three groups. However, the ex vivo and in vivo OPG gene therapies significantly increased the implant stability. The pulling forces of 21.56±2.44 and 18.19±2.10 N were required to dissociate the pin implants from tibiae, respectively (Figure 2). There was no statistical difference between the two OPG gene-modified groups.


Cell-based osteoprotegerin therapy for debris-induced aseptic prosthetic loosening on a murine model.

Zhang L, Jia TH, Chong AC, Bai L, Yu H, Gong W, Wooley PH, Yang SY - Gene Ther. (2010)

Summary of maximum pulling force required to pull out the implants at 4 weeks following treatments (* p<0.05). The insert illustrates an example trace of pulling forces applied to extract the pin implant from the surrounding bone.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2914841&req=5

Figure 2: Summary of maximum pulling force required to pull out the implants at 4 weeks following treatments (* p<0.05). The insert illustrates an example trace of pulling forces applied to extract the pin implant from the surrounding bone.
Mentions: The implanted pin pull-out test was performed to examine the mechanical stability of the implant following wear debris challenge and gene therapy. The average peak interfacial shear strength against pulling was 10.34±2.05, 8.14±1.23 and 7.32±1.35 N in AAV-LacZ, FLS-AAV-LacZ and virus-free non-treated groups respectively. There was no statistical difference between the three groups. However, the ex vivo and in vivo OPG gene therapies significantly increased the implant stability. The pulling forces of 21.56±2.44 and 18.19±2.10 N were required to dissociate the pin implants from tibiae, respectively (Figure 2). There was no statistical difference between the two OPG gene-modified groups.

Bottom Line: Biomechanical pullout test indicated a significant restoration of implant stability after the cell-based OPG gene therapy.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.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.

View Article: PubMed Central - PubMed

Affiliation: Orthopaedic Research Institute, Via Christi Regional Medical Center, 929 N St Francis Street, Wichita, KS 67214, USA.

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.

Show MeSH
Related in: MedlinePlus