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Combined depletion of interleukin 1 and interleukin 6 does not exceed single depletion of interleukin 1 in TNF mediated arthritis
  1. Silvia Hayer1,
  2. Birgit Niederreiter1,
  3. Josef Smolen1,
  4. Kurt Redlich1
  1. 1Department of Internal Medicine III, Division of Rheumatology, Medical University of Vienna, Vienna, Austria

Abstract

Background Previous studies demonstrated a regulatory role of interleukin 1 (IL-1) in inflammatory cartilage damage and bone destruction in human tumour necrosis factor transgenic (hTNFtg) mice, an animal model for rheumatoid arthritis. Moreover, blocking of IL-6 has been shown to reduce local bone erosions in this model. Therefore the authors wanted to investigate the effect of a combined depletion of IL-1 and IL-6 on the development and severity of inflammatory, erosive arthritis.

Methods The authors first crossed IL-1α and ß deficient (IL-1−/−) mice with IL-6−/− mice to generate IL-1−/−IL-6−/− double knockout mice. The authors next intercrossed these animals with arthritogenic hTNFtg mice to receive IL-1−/−IL-6−/−hTNFtg mice. The authors weekly assessed clinical signs of arthritis in hTNFtg, IL-1−/−hTNFtg mice, IL-6−/−hTNFtg mice and IL-1−/−IL-6−/−hTNFtg mice starting from week 4 after birth until week 16. The authors stained decalcified paw sections from all four genotypes with H&E to determine the amount of inflammatory synovial pannus formation, with tartrate-resistant acid phosphatase (TRAP) 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 The authors found a significant reduction in the clinical signs of arthritis, indicated by an increase of paw swelling and a decrease in grip strength, in IL-1−/−IL-6−/−hTNFtg mice when compared to their hTNFtg littermates. In line with these findings the authors observed a significant decrease in synovial inflammation in IL-1−/−IL-6−/−hTNFtg mice when compared to hTNFtg animals. Moreover, the number of synovial TRAP+ osteoclasts was markedly diminished in IL-1−/−IL-6−/−hTNFtg mice and reduced osteoclast formation was accompanied by significantly less subchondral bone erosions. Additionally, the authors found a conserved articular cartilage structure showing almost no cartilage degradation in IL-1−/−IL-6−/−hTNFtg mice compared to their hTNFtg littermates. In IL-1−/−IL-6−/−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 IL-6−/−hTNFtg mice. However, by comparing IL-1−/−IL-6−/−hTNFtg mice with IL-1−/−hTNFtg mice the authors found a similar reduction on synovial inflammation, as well as subchondral bone erosions and articular cartilage destruction.

Conclusion The phenotype of IL-1−/−IL-6−/−hTNFtg mice does not differ from IL-1−/−hTNFtg animals indicating no synergistic effects when IL-1 and IL-6 is simultaneously blocked in TNF mediated arthritis.

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