Das LIM-Domänen Protein FHL2 als neuer Regulator des aggressiv-invasiven Verhaltens synovialer Fibroblasten bei rheumatoider Arthritis.
Final Report Abstract
This project was designed to answer the following questions: 1. What factors (part. cytokines and growth factors) mediate the increased expression of FHL2 in RA-FLS and what signaling pathways are involved? Does the inhibition of individual signaling pathways (e.g., MAPK, PI3K, IKK-NFκB) result in a reduced FHL2 production and what conclusions can be drawn about the regulation of FHL2 in RA-FLS? 2. What is the kinetics of FHL2 expression the course of the RA- like, destructiv arthritis in TNFalpha- dependent animal models the disease? 3. What are the mechanisms by which FHL2 inhibits the TNFalpha induced expression of MMPs and, thereby, the aggressive bahaviour of synovial fibroblasts, and what potential therapeutic approaches can be derived? 4. What are the consequences of a loss of FHL2 for the susceptibility and severity of experimental, TNFalpha depdendent arthritides, e.g., in hTNFtg/FHL2-/- mice? All together, most of the questions could be answered in the course of the project. In summary, the ihTNFtg mouse displays on doxycycline administration the major features of inflammatory arthritis disease. It represents a unique animal model for studying the molecular mechanisms of arthritis, especially for the early phases of disease genesis and tissue remodeling steps on abrogation of TNFalpha expression. Furthermore, unlimited crossing of the ihTNFtg mice with various knockout or transgenic mice opens new possibilities for unraveling the role of various signaling molecules acting in concert with TNFα.
