Preceding scientific studies demonstrated a regulatory role of interleukin 1 in inflammatory cartilage harm and bone destruction in human tumor necrosis issue transgenic mice, an animal model for Rheumatoid Arthritis. In addition, blocking of IL 6 is shown to reduce local bone erosions within this model. For that reason we desired to investigate the result jak stat of the mixed depletion of IL 1 and IL 6 about the improvement and severity of inflammatory, erosive arthritis. Approaches: We 1st crossed IL1a and deficient mice with IL6 / mice to create 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 up from week 4 after birth until week 16.
We stained decalcified paw sections from all 4 genotypes with hematoxylin&eosin to determine the amount of inflammatory synovial pannus formation, with tartrate resistant acid phosphatase to evaluate the number of synovial osteoclasts and the occurrence of subchondral bone erosions, with toluidine blue BYL719 solubility to assess articular cartilage harm. Quantitative analysis of histopathological changes were performed using the Osteomeasure Software System. Results: We found a significant reduction in the clinical indicators 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.
In addition, the number of synovial TRAP osteoclasts was markedly diminished in IL1 / IL6 / hTNFtg mice and reduced osteoclast formation, was accompanied by Gene expression significantly less subchondral bone erosions. Additionally, we found a conserved articular cartilage structure showing almost no cartilage degradation in IL1 / IL6 / 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 injury 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.
Conclusion: 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 high throughput screening TNF mediated arthritis. Rheumatoid Arthritis is a chronic inflammatory joint disease and characterized by synovial hyperplasia. We previously cloned an E3 ubiquitin ligase, Synoviolin, as a regulatory factor of cell proliferation. It suggested that endoplasmic reticulum associated degradation system via Synoviolin has important roles for overgrowth of synoviocytes.