Background: Periprosthetic tissue formation and local inflammation
that are associated with wear debris contribute to the pathogenesis of aseptic
loosening of a prosthesis. This study evaluated a retrovirus-mediated gene
therapy with use of a novel xenograft-based animal model.
Methods: Human periprosthetic tissues obtained from patients during
revision arthroplasty performed because of aseptic loosening of a prosthetic
joint were transplanted into the left quadriceps and paravertebral muscles of
severe combined immunodeficient (SCID) mice. The engrafted tissues were
recovered seven, fifteen, or thirty days after implantation for histological
and molecular analyses. The periprosthetic tissues were incubated with
retroviruses encoding for human interleukin-1 receptor antagonist (hIL-1Ra) or
bacteria ß-galactosidase (LacZ) at 37°C for three hours prior to
implantation to evaluate their responses to gene modification.
Results: The human periprosthetic tissues were well accepted in SCID
mice for up to thirty days, with angiogenesis occurring in the majority of the
implanted tissue sections. The histological appearance was consistent between
the recovered graft tissue and the original donor tissue. Strong expression of
interleukin-1, tumor necrosis factor, and interleukin-6 was detected in the
xenografts with use of immunohistochemical stains. Histological analysis
revealed that interleukin-1 receptor antagonist gene modification
significantly decreased the total number of inflammatory cells (p < 0.01)
in engrafted human tissue containing implant wear debris. Real-time reverse
transcription-polymerase chain reaction and immunohistochemical staining
showed declining expression levels of interleukin-1 and tumor necrosis factor
following interleukin-1 receptor antagonist gene transfer in comparison with
LacZ-transduced or virus-free controls.
Conclusions: Human periprosthetic tissue can survive in the SCID
mouse host for up to thirty days and responds to the interleukin-1 receptor
antagonist gene transfer with the amelioration of inflammation.
Clinical Relevance: The human periprosthetic tissue-SCID mouse
chimera has been characterized in this study as a useful model to explore the
properties of human periprosthetic tissue in vivo, laying the foundation for
potential clinical application of gene therapy in aseptic loosening.