Limits...
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.

Show MeSH

Related in: MedlinePlus

Histological appearance of the pin-implanted tibiae at 4 weeks following in vivo and ex vivo gene modifications: (A) in vivo AAV-OPG treated; (B) cell-based FLS-AAV-OPG therapy; (C) in vivo AAV-LacZ injected; (D) FLS-AAV-LacZ transfused; (E) virus-free non-treated control. Panel (F) illustrates the comparison of periprosthetic membrane thickness among the five groups (** p< 0.01).
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2914841&req=5

Figure 3: Histological appearance of the pin-implanted tibiae at 4 weeks following in vivo and ex vivo gene modifications: (A) in vivo AAV-OPG treated; (B) cell-based FLS-AAV-OPG therapy; (C) in vivo AAV-LacZ injected; (D) FLS-AAV-LacZ transfused; (E) virus-free non-treated control. Panel (F) illustrates the comparison of periprosthetic membrane thickness among the five groups (** p< 0.01).

Mentions: Histological evaluation on cross-sections of prosthetic tibiae revealed ubiquitous presence of inflammatory fibrous membranes at the bone-implant interface in both FLS-AAV-LacZ and non-treated control groups. However, the interface membranes in sections from the FLS-AAV-OPG group were dramatically thinner, and even resolved in many of the samples. Figure 3 illustrates a typical micrograph of peri-implant pseudo-membranes among the groups, and Figure 3F summarizes the measurements of membrane thickness, indicating that both in vivo and ex vivo OPG gene transfer significantly blocked the periprosthetic membrane formation. There was no significant difference between the two OPG treated groups with respect to interfacial membrane thickness (Figure 3). Modified Trichrome staining was performed to reveal changes in bone collagen content.16 While the periprosthetic bone tissues from AAV-LacZ, FLS-AAV-LacZ and virus-free groups generally exhibited weak staining of Trichrome blue coloration, OPG-gene modification using in vivo or ex vivo delivery markedly enhanced the staining as seen previously.17 Quantified intensity analysis by computerized image analysis system confirmed the statistical significance (P<0.01, Figure 4).


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)

Histological appearance of the pin-implanted tibiae at 4 weeks following in vivo and ex vivo gene modifications: (A) in vivo AAV-OPG treated; (B) cell-based FLS-AAV-OPG therapy; (C) in vivo AAV-LacZ injected; (D) FLS-AAV-LacZ transfused; (E) virus-free non-treated control. Panel (F) illustrates the comparison of periprosthetic membrane thickness among the five groups (** p< 0.01).
© Copyright Policy
Related In: Results  -  Collection

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

Figure 3: Histological appearance of the pin-implanted tibiae at 4 weeks following in vivo and ex vivo gene modifications: (A) in vivo AAV-OPG treated; (B) cell-based FLS-AAV-OPG therapy; (C) in vivo AAV-LacZ injected; (D) FLS-AAV-LacZ transfused; (E) virus-free non-treated control. Panel (F) illustrates the comparison of periprosthetic membrane thickness among the five groups (** p< 0.01).
Mentions: Histological evaluation on cross-sections of prosthetic tibiae revealed ubiquitous presence of inflammatory fibrous membranes at the bone-implant interface in both FLS-AAV-LacZ and non-treated control groups. However, the interface membranes in sections from the FLS-AAV-OPG group were dramatically thinner, and even resolved in many of the samples. Figure 3 illustrates a typical micrograph of peri-implant pseudo-membranes among the groups, and Figure 3F summarizes the measurements of membrane thickness, indicating that both in vivo and ex vivo OPG gene transfer significantly blocked the periprosthetic membrane formation. There was no significant difference between the two OPG treated groups with respect to interfacial membrane thickness (Figure 3). Modified Trichrome staining was performed to reveal changes in bone collagen content.16 While the periprosthetic bone tissues from AAV-LacZ, FLS-AAV-LacZ and virus-free groups generally exhibited weak staining of Trichrome blue coloration, OPG-gene modification using in vivo or ex vivo delivery markedly enhanced the staining as seen previously.17 Quantified intensity analysis by computerized image analysis system confirmed the statistical significance (P<0.01, Figure 4).

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