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

L. Zhang, T. H. Jia, Alexander Chong, L. Bai, H. Yu, W. Gong, P. H. Wooley, S. Y. Yang

Research output: Contribution to journalArticle

24 Citations (Scopus)

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 phosphataseosteoclasts 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.

Original languageEnglish (US)
Pages (from-to)1262-1269
Number of pages8
JournalGene Therapy
Volume17
Issue number10
DOIs
StatePublished - Oct 1 2010

Fingerprint

Osteoprotegerin
Osteolysis
Therapeutics
Titanium
Transgenes
Genetic Therapy
Genes
Prosthesis Failure
Knee Prosthesis
Gene Transfer Techniques
Knee Replacement Arthroplasties
Weight-Bearing
Tibia
Interleukin-1
Histology
Carcinogenesis
Tumor Necrosis Factor-alpha
Fibroblasts
Joints
Control Groups

Keywords

  • aseptic loosening
  • cell-based therapy
  • implant stability
  • osteoprotegerin
  • periprosthetic osteolysis

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

Cite this

Cell-based osteoprotegerin therapy for debris-induced aseptic prosthetic loosening on a murine model. / Zhang, L.; Jia, T. H.; Chong, Alexander; Bai, L.; Yu, H.; Gong, W.; Wooley, P. H.; Yang, S. Y.

In: Gene Therapy, Vol. 17, No. 10, 01.10.2010, p. 1262-1269.

Research output: Contribution to journalArticle

Zhang, L, Jia, TH, Chong, A, Bai, L, Yu, H, Gong, W, Wooley, PH & Yang, SY 2010, 'Cell-based osteoprotegerin therapy for debris-induced aseptic prosthetic loosening on a murine model', Gene Therapy, vol. 17, no. 10, pp. 1262-1269. https://doi.org/10.1038/gt.2010.64
Zhang, L. ; Jia, T. H. ; Chong, Alexander ; Bai, L. ; Yu, H. ; Gong, W. ; Wooley, P. H. ; Yang, S. Y. / Cell-based osteoprotegerin therapy for debris-induced aseptic prosthetic loosening on a murine model. In: Gene Therapy. 2010 ; Vol. 17, No. 10. pp. 1262-1269.
@article{38faba9b31264cc18013601ca3ce9082,
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 phosphataseosteoclasts 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.",
keywords = "aseptic loosening, cell-based therapy, implant stability, osteoprotegerin, periprosthetic osteolysis",
author = "L. Zhang and Jia, {T. H.} and Alexander Chong and L. Bai and H. Yu and W. Gong and Wooley, {P. H.} and Yang, {S. Y.}",
year = "2010",
month = "10",
day = "1",
doi = "10.1038/gt.2010.64",
language = "English (US)",
volume = "17",
pages = "1262--1269",
journal = "Gene Therapy",
issn = "0969-7128",
publisher = "Nature Publishing Group",
number = "10",

}

TY - JOUR

T1 - Cell-based osteoprotegerin therapy for debris-induced aseptic prosthetic loosening on a murine model

AU - Zhang, L.

AU - Jia, T. H.

AU - Chong, Alexander

AU - Bai, L.

AU - Yu, H.

AU - Gong, W.

AU - Wooley, P. H.

AU - Yang, S. Y.

PY - 2010/10/1

Y1 - 2010/10/1

N2 - 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 phosphataseosteoclasts 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.

AB - 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 phosphataseosteoclasts 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.

KW - aseptic loosening

KW - cell-based therapy

KW - implant stability

KW - osteoprotegerin

KW - periprosthetic osteolysis

UR - http://www.scopus.com/inward/record.url?scp=77957990313&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77957990313&partnerID=8YFLogxK

U2 - 10.1038/gt.2010.64

DO - 10.1038/gt.2010.64

M3 - Article

VL - 17

SP - 1262

EP - 1269

JO - Gene Therapy

JF - Gene Therapy

SN - 0969-7128

IS - 10

ER -