Viral interleukin‐10 gene inhibition of inflammation,osteoclastogenesis, and bone resorption in response to titanium particles

Objective

To evaluate the potential of viral interleukin‐10 (vIL‐10) gene therapy as an approach to prevent wear debris–induced inflammation, osteoclastogenesis, and bone resorption as it relates to periprosthetic osteolysis in patients with total joint replacements.

Methods

Replication‐defective adenovirus vectors expressing vIL‐10 (AdvIL‐10) or LacZ (AdLacZ) target genes were used to transduce fibroblast‐like synoviocytes (FLS) in vitro, and the effects of these cells on wear debris–induced proinflammatory cytokine production and receptor activator of nuclear factor κB ligand + macrophage colony‐stimulating factor splenocyte osteoclastogenesis were assessed by enzyme‐linked immunosorbent assay and tartrate‐resistant acid phosphatase assay. The effects of AdvIL‐10 administration on wear debris–induced osteolysis in vivo were analyzed using the mouse calvaria model, in which AdLacZ was used as the control.

Results

In the presence of AdLacZ‐infected FLS, titanium particle–stimulated macrophages exhibited a marked increase in secretion of tumor necrosis factor α (TNFα) (6.5‐fold), IL‐6 (13‐fold), and IL‐1 (5‐fold). Coculture with AdvIL‐10–transduced FLS suppressed cytokine secretion to basal levels, while addition of an anti–IL‐10 neutralizing antibody completely blocked this effect. The vIL‐10–transduced FLS also inhibited osteoclastogenesis 10‐fold in an anti–IL‐10–sensitive manner. In vivo, titanium implantation resulted in a 2‐fold increase in osteoclasts (P < 0.05) and in a 2‐fold increase in sagittal suture area (P < 0.05). This increase over control levels was completely blocked in mice receiving intraperitoneal injections of AdvIL‐10, all of whom had measurable serum vIL‐10 levels for the duration of the experiment. Immunohistochemistry demonstrated reduced cyclooxygenase 2 and TNFα expression in AdvIL‐10–infected animals.

Conclusion

This study demonstrates that gene delivery of vIL‐10 inhibits 3 processes critically involved in periprosthetic osteolysis: 1) wear debris–induced proinflammatory cytokine production, 2) osteoclastogenesis, and 3) osteolysis.