Cell type specific action of glucocorticoids in inflammation and bone integrity of rheumatoid arthritis

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Rheumatoid arthritis (RA) is a severe chronic inflammation of the joints which is accompanied by joint destruction and bone loss. Because of their potent anti-inflammatory action, glucocorticoids (GCs) are among the main therapeutic drugs used for treatment of RA. Their usefulness is however hampered by the fact that chronic GC treatment causes osteoporosis as one of the side effects.Although GCs have been in use for 60 years, it is not yet known which cell types and which molecular mechanisms are responsible for the beneficial effects and which ones are involved in the expression of the side effects of GC treatment in RA. The aim of this proposal is to determine the cell types involved in the influence of steroids on inflammation and on bone architecture in the context of rheumatoid arthritis.In our preliminary work we exploited conditional glucocorticoid receptor (GR) mutant mice in acute rheumatoid arthritis and GC induced osteoporosis models. We demonstrated that the GR is essential in T cells for mediating steroid-induced suppression of acute inflammation in antigen induced arthritis, but is dispensable in myeloid cells. Furthermore we showed that homo-dimerization of the GR is important for this process. In GC induced osteoporosis we found that monomeric GR in osteoblasts is sufficient to mediate this side effect, presumably via suppression of cytokine expression in the osteoblasts.With these results we now have the tools in hand to address the following questions, which are essential for the understanding of GC action in steroid therapy of RA:1. Is the presence of the GR dimer in certain T cell subsets required for antiinflammatory GC effects in RA?2. Do GCs also influence bone remodelling in RA by affecting T cells?3. Do GCs influence bone turnover and the inflammatory response in RA by affecting cytokine expression of non-hematopoietic cells (e.g. osteoblasts, adipocytes and synovial cells)?Using an approach with conditional GR mutant mice and co-culture experiments of primary immune and mesenchymal cells, we expect to gain a detailed understanding of the complex mechanisms involved in steroid therapy of an inflammatory bone disease. Our research program is well embedded in the fields of immunological diseases and bone diseases by our own expertise and co-operations with experts in these areas. Our findings will be fundamental to improve steroid therapy of rheumatoid arthritis and to develop novel treatment paradigms for this severe chronic disease. We therefore strongly feel that this program is suitable for the priority program “Immunobone-Osteoimmunology”.