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

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 B 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 ␣ (TNF␣) (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 TNF␣ 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.

Protective effects of IL-1Ra or vIL-10 gene transfer on a murine model of wear debris-induced osteolysis

“…35 In this study, elevated vIL-10 expression dramatically reduced the incidence of bone pit erosions and bone collagen degradation, along with marked anti-inflammatory effects. Carmody et al 22 recently published findings, which show that systemic viral IL-10 gene transfer completely blocked titanium particle-induced calvaria bone resorption, which is in agreement with current results. …”

“…Blocking these processes may provide potential therapeutic approaches to prevent or retard the periprosthetic osteolysis and prolong the life of prostheses. 22 We have proposed that the inhibition of proinflammatory cytokines represents a potential therapy to reduce chronic inflammation provoked by wear debris in the periprosthetic tissue. Current systemic anti-inflammation therapies have several weaknesses, including high-dose requirements with modest efficiency, systemic side effects, and tendency for poor patient compliance.…”

Periprosthetic osteolysis: genetics, mechanisms and potential therapeutic interventions

“…41 IL-6 (-/-) and IL-1R (-/-) mice. In terms of drug and gene therapy, several substances have been evaluated: alendronate and pentoxifylline, 30 etanercept celecoxib, 39 RANK:Fc, 41 OPG, 42,43 TNFR:Fc, 40 viral IL (vIL)-10 44 anti-IL-6 and anti-IL-1R. These have elucidated the biological hierarchy in which RANK blockade is clearly the safest and most effective means to prevent and ameliorate wear debris-induced osteolysis.…”

“…Furthermore, the incidence of bone pit erosions and bone collagen degradation was dramatically reduced. Carmody and colleagues 44 used replication-defective adenovirus vectors expressing vIL-10 (AdvIL-10) or LacZ (AdLacZ) target genes to transduce fibroblast-like synoviocytes (FLS) in vitro to evaluate wear debris-induced osteolysis in a mouse calvaria model. In the presence of AdLacZ-infected FLS, titanium particle-stimulated macrophages exhibited a marked increase in secretion of TNFα (6.5-fold), IL-6 (13-fold) and IL-1 (5-fold).…”

Aseptic loosening

“…79,80 In the air pouch study, an investigation of mRNA expression using real-time PCR was conducted to determine whether anti-inflammatory gene therapy affects cytokine gene expression. IL-1, IL-6 and TNF gene expression were readily detected by the technique, and IL-1 was observed to be the predominant cytokine expressed in response to UHMWPE particle stimulation.…”