Anti-tumor necrosis factor therapy increases synovial osteoprotegerin expression in rheumatoid arthritis.
OBJECTIVE
Treatment of rheumatoid arthritis (RA) with tumor necrosis factor (TNF)-blocking agents, including etanercept and infliximab, has resulted in reductions in the radiographic progression of RA. However, the exact mechanism by which this protection occurs has not been determined. In order to add to such knowledge, we investigated the effect of anti-TNF therapy on the expression of osteoprotegerin (OPG) and receptor activator of NF-kappaB ligand (RANKL) in synovial tissue.


METHODS
The expression of OPG and RANKL in synovial biopsy specimens was evaluated by immunohistochemistry. Serial synovial biopsy specimens were obtained from 18 patients with RA, before and after treatment with etanercept (9 patients) or infliximab (9 patients). Biopsy specimens were evaluated by double-blind semiquantitative analysis and image analysis. The in vitro effect of TNF antagonists on the RANKL/OPG expression in osteoblasts and endothelial cells was evaluated by Western blotting. Statistical analysis was performed using Wilcoxon's signed rank test, followed by the Bonferroni correction for multiple comparisons of paired samples. The results of in vitro experiments were evaluated by one-way analysis of variance, with Tukey's post hoc test.


RESULTS
Treatment with both infliximab and etanercept increased the expression of OPG in synovial tissue. After 8 weeks of treatment, neither infliximab nor etanercept influenced RANKL expression. In both groups of patients, the RANKL:OPG ratio decreased following therapy. In vitro, both of the TNF antagonists mimicked the in vivo effect, inducing a decrease in the RANKL:OPG ratio in TNF-primed osteoblasts and endothelial cells.


CONCLUSIONS
Therapy with TNF antagonists in RA modulates the OPG/RANKL system, a potential mechanism that could explain the retardation of radiographic damage observed following anti-TNF therapy.
Catrina
Anca Irinel
AI
Rheumatology Research Laboratory, Karolinska University Hospital, Karolinska Institutet, S-17176 Stockholm, Sweden. Anca.Catrina@ki.se
af Klint
Erik
E
Ernestam
Sofia
S
Catrina
Sergiu-Bogdan
SB
Makrygiannakis
Dimitrios
D
Botusan
Ileana Ruxandra
IR
Klareskog
Lars
L
Ulfgren
Ann-Kristin
AK
D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use*; D018501:Antirheumatic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy*; D002352:Carrier Proteins / Q000096:biosynthesis*; D000068800:Etanercept; D005260:Female; D006023:Glycoproteins / Q000096:biosynthesis*; D006801:Humans; D007074:Immunoglobulin G / Q000494:pharmacology / Q000627:therapeutic use*; D000069285:Infliximab; D008297:Male; D008562:Membrane Glycoproteins / Q000096:biosynthesis*; D008875:Middle Aged; D053244:Osteoprotegerin; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D018160:Receptors, Cytoplasmic and Nuclear / Q000096:biosynthesis*; D018124:Receptors, Tumor Necrosis Factor / Q000096:biosynthesis* / Q000627:therapeutic use*; D013583:Synovial Membrane / Q000187:drug effects* / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*
D000911:Antibodies, Monoclonal; D018501:Antirheumatic Agents; D002352:Carrier Proteins; D006023:Glycoproteins; D007074:Immunoglobulin G; D008562:Membrane Glycoproteins; D053244:Osteoprotegerin; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; C505686:TNFRSF11A protein, human; C506030:TNFRSF11B protein, human; C505688:TNFSF11 protein, human; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab; D000068800:Etanercept