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Distinct patterns of RANKL/osteoprotegerin system modulation through anti-tumour necrosis factor and corticosteroid therapy in rheumatoid arthritis synovium

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Anti-tumour necrosis factor (TNF) therapy with both etanercept and infliximab decreases radiographic progression of patients with rheumatoid arthritis (RA), while the effect of local corticosteroid injections, a routine adjuvant therapy in arthritis, on bone metabolism is still debated. Thus, we investigated the effect of both anti-TNF and local corticosteroid therapy on synovial expression of osteoprotegerin (OPG) and receptor activator of NF-κB ligand (RANKL).


OPG and RANKL were evaluated by immunohistochemistry in serial synovial biopsies obtained from 18 RA patients before and after 8 weeks of treatment with etanercept (nine patients) or infliximab (nine patients). Eighteen additional patients with arthritis that received a local corticosteroid injection were evaluated before and after 2 weeks of the injection. Biopsies were evaluated by double-blind semi-quantitative analysis and image analysis. The in vitro effect of TNF antagonists and corticosteroids (dexametasone) on RANKL/OPG expression in osteoblasts was evaluated by western blot. Statistical analysis was performed using the Wilcoxon's signed-rank test followed by Bonferroni correction.


OPG was present in all biopsies with a characteristic pattern restricted mainly to the endothelial cells and few mononuclear cells. RANKL was present mainly in the T-cell area and to a lesser extent on some endothelial cells, but absent in other mononuclear cells. Treatment with both infliximab and etanercept increased synovial OPG expression. Neither infliximab nor etanercept influenced RANKL expression following 8 weeks of treatment. The RANKL/OPG ratio decreased following therapy in both groups, the effect being more pronounced in the responders as compared with non-responders to therapy. Local corticosteroid treatment resulted in a similar change of the RANKL/OPG ratio through a different mechanism, with a significant decrease of the synovial RANKL and no changes in the OPG expression. In vitro both TNF antagonists and corticosteroids mimicked the in vivo effect inducing a decrease in the RANKL/OPG ratio in TNF-primed osteoblasts.


Therapy with both TNF antagonists and local corticosteroids modulates the RANKL/OPG system, inhibiting bone destruction through distinct mechanisms. Thus, association of these two therapies may be beneficial in preventing bone erosions in RA.

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  • Rheumatoid Arthritis
  • Infliximab
  • Etanercept
  • Rheumatoid Arthritis Synovium
  • RANKL Expression