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 kappaB 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 alpha (TNFalpha) (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 TNFalpha 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.

• Authors: Emily E Carmody, Edward M Schwarz, J Edward Puzas, Randy N Rosier, Regis J O'Keefe
• Journal: Arthritis and rheumatism (Arthritis Rheum) Vol. 46 Issue 5 Pg. 1298-308 (May 2002) ISSN: 0004-3591 [Print] United States
• PMID: 12115237 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• BCRF1 protein, Human herpesvirus 4
• Interleukin-1
• Interleukin-6
• Tumor Necrosis Factor-alpha
• Viral Proteins
• Interleukin-10
• Titanium

Topics

• Adenoviridae (genetics)
• Animals
• Cells, Cultured
• Fibroblasts (cytology)
• Genetic Therapy
• Genetic Vectors
• Inflammation (chemically induced, therapy)
• Interleukin-1 (biosynthesis)
• Interleukin-10 (genetics)
• Interleukin-6 (biosynthesis)
• Macrophages (drug effects, metabolism)
• Osteoclasts (immunology)
• Osteolysis (chemically induced, immunology, therapy)
• Skull (cytology, immunology)
• Spleen (cytology)
• Synovial Membrane (cytology)
• Titanium (immunology, pharmacology)
• Transduction, Genetic
• Transgenes (immunology)
• Tumor Necrosis Factor-alpha (biosynthesis)
• Viral Proteins (genetics)