Former studies demonstrated a regulatory cyclic peptide synthesis function of interleukin 1 in inflammatory cartilage harm and bone destruction in human tumor necrosis factor transgenic mice, an animal model for Rheumatoid Arthritis. Also, blocking of IL 6 is shown to cut back local bone erosions in this model. For that reason we wished to investigate the impact of a combined depletion of IL 1 and IL 6 on the development and severity of inflammatory, erosive arthritis. We initial crossed IL1a and deficient mice with IL6 / mice to make IL1 / IL6 / double knockout mice. We next intercrossed these animals with arthritogenic hTNFtg mice to receive IL1 / IL6 / hTNFtg mice. We weekly assessed clinical signs of arthritis in hTNFtg, IL1 / hTNFtg mice, IL6 / hTNFtg mice and IL1 / IL6 / hTNFtg mice starting from week 4 just after birth till week 16.

We stained decalcified paw sections from all 4 genotypes with hematoxylin&eosin to determine the amount of inflammatory synovial reversible AMPK activator pannus formation, with tartrate resistant acid phosphatase to evaluate the number of synovial osteoclasts and the occurrence of subchondral bone erosions, with toluidine blue to assess articular cartilage damage. Quantitative analysis of histopathological changes were performed using the Osteomeasure Software System. Results: We found a significant reduction in the clinical signs of arthritis, indicated by an increase of paw swelling and a decrease in grip strength, in IL1 / IL6 / hTNFtg mice when compared to their hTNFtg littermates. In line with these findings we observed a significant decrease in synovial inflammation in IL1 / IL6 / hTNFtg mice when compared to hTNFtg animals.

Moreover, the number of Metastatic carcinoma synovial TRAP osteoclasts was markedly diminished in IL1 / IL6 / hTNFtg mice and reduced osteoclast formation, was accompanied by significantly less subchondral bone erosions. Additionally, we found a conserved articular cartilage structure showing almost no cartilage degradation in IL1 / IL6 / Caspase activity hTNFtg mice compared to their hTNFtg littermates. In IL1 / IL6 / hTNFtg mice clinical, as well as, histological signs of disease, including joint inflammation, bone destruction and cartilage damage were also significantly diminished when compared to IL6 / hTNFtg mice. However, by comparing IL1 / IL6 / hTNFtg mice with IL1 / hTNFtg mice we found a similar reduction on synovial inflammation, as well as subchondral bone erosions and articular cartilage destruction. The phenotype of IL1 / IL6 / hTNFtg mice does not differ from IL1 / hTNFtg animals indicating no synergistic effects when IL 1 and IL 6 is simultaneously blocked in TNF mediated arthritis.