Anti-tumour necrosis factor therapy modulates the OPG/OPGL system in rheumatoid arthritis synovium

Osteoprotegerin (OPG) is a soluble decoy receptor that acts as a receptor antagonist, blocking OPG ligand (OPGL) induced osteoclastogenesis. In vitro, proinflammatory cytokines such as tumour necrosis factor (TNF) upregulate endothelial OPG expression. However, low levels of endothelial OPG expression are seen in synovial biopsies from patients with active rheumatoid arthritis (RA) associated with high levels of TNF. In order to elucidate the in vivo interaction between TNF and the OPG/OPGL system in RA, we investigated the effect of anti-TNF therapy on synovial expression of OPG and OPGL.

OPG, OPGL and CD31 were evaluated by immunohistochemistry in serial synovial biopsies obtained from 20 RA patients before and after 8 weeks of treatment with Etanercept (Amgen and Wyeth Pharmaceuticals, USA) or Infliximab (Schering-Plough, Stockholm, Sweden). Biopsies were evaluated by double-blind semiquantitative analysis and image analysis. Statistical analysis was performed using the Wilcoxon's signed-rank test followed by Bonferroni corrections for multiple comparisons.

OPG was expressed in all studied synovial biopsies, mainly in the CD31-positive endothelial cells. OPGL expression was detected in synovial areas rich in T cells, with low expression in endothelial cells and macrophages. Treatment with Infliximab significantly increased synovial OPG expression whereas the increase in synovial OPG expression observed after Etanercept treatment did not reach statistical significance. Neither infliximab nor etanercept influenced OPGL expression following 8 weeks of treatment. The ratio between synovial OPGL and OPG expression decreased following treatment with infliximab (P < 0.05, after Bonferroni comparisons) and etanercept (NS after Bonferroni correction).

Our findings suggest a particular OPG–TNF interaction in vivo as well as a potential difference in action between the two anti-TNF agents tested.