The role of IL-1 in TNF induced erosive arthritis

Rheumatoid arthritis (RA) is the most prevalent inflammatory rheumatic disease. RA patients suffer not only from painful joint swelling, but also from local as well as systemic bone destruction, representing a major reason for progressive disability. There is overwhelming evidence that the proinflammatory cytokine tumor necrosis factor alpha (TNF) plays a central role in the pathogenesis of RA. Indeed, studies in genetically altered mice overexpressing human TNF (hTNFtg) suggest that TNF directly contributes to the pathogenesis of the disease. Thus, hTNFtg mice develop spontaneous arthritis with all signs of human RA including chronic synovial inflammation, cartilage and bone destruction. Even more relevant, blocking of TNF has proven efficacious in reducing inflammation and joint destruction in RA patients, especially when combined with methotrexate (MTX). Blocking of TNF alone however is usually not sufficient to achieve remission of RA. Among several proinflammatory cytokines, which are induced by TNF, interleukine 1 (IL-1) appears to be of major importance. Since IL-1 blockade is also effective in the treatment of RA, IL1-mediated effects may participate importantly in the disease process. To address the importance of IL-1 as a mediator of TNF-dependent joint disease, we want to generate a model of TNF overxpression with concomitant complete lack of IL-1 by intercrossing hTNFtg mice with IL-1 a/ß double deficient (KO) mice. The following groups of mice (wildtype, IL-1a/ßKO, hTNFtg, IL- 1a/ßKO/hTNFtg) will be evaluated for clinical signs of arthritis. Furthermore detailed histological analyses assessing the degree of synovial inflammation, cartilage- and bone destruction will be performed. Given the important role of bone turnover in the pathogenesis of inflammatory bone loss, detailed ex vivo analyses of osteoblast and osteoclast function under TNF transgenic conditions in the absence and presence of IL-1 will be performed. Moreover systemic changes of bone formation and resorption will be assessed by quantitative computed tomography and bone histomorphometry. In addition, bone marrow transfer experiments will be performed to determine the cellular source of IL-1. Finally mice will also be treated with MTX and a combination of MTX and anti-TNF to evaluate if MTX affects IL-1 production in the context of hTNFtg arthritis. In summary, this study aims to clarify the relevance of IL-1 in TNF-mediated erosive joint disease and will therefore influence future therapeutic concepts of RA, such as combination therapy.