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

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Abstract
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.