Title of the thesis: Development and Testing of Translational Ex Vivo Models for use in Drug Development in Inflammatory Osteoarthritis and Rheumatoid Arthritis
Abstract
There is a need to develop novel treatments for osteoarthritis and rheumatoid arthritis that affect the underlying destruction of the joint. However, the number of novel developed treatments that have been approved is currently close to zero for osteoar-thritis and slightly better for rheumatoid arthritis, but still too low. It is therefore important to develop tools that can be used to monitor the structural effects early in development and allow translation of these results to the early clinical studies. The goal of this thesis was to develop joint tissue cultures together with biomarkers of tissue degradation and formation, which could be used to investigate the structural degradation of the main joint tissues: bone, cartilage, and synovium. Such models could be used to test the protective effect of novel treatments on structural degrada-tion and thereby be candidates to continue on in development. Translational of the effect measured in the laboratory models into human was believed to be possible due to the biomarkers, which can be measured in laboratory models and humans. This allows measurement the same output in different settings. In this thesis, a tissue culture model was developed to monitor inflammation driven degradation of the synovium. This model was found to be better than isolated cells from the synovium grown on collagens. Additionally, this thesis used a model of inflammatory cartilage degradation to investigate if anti-inflammatory rheumatoid arthritis treatments could have cartilage protective effect and be potential treatments for inflammation-driven osteoarthritis. Two cellular pro-inflammatory signalling molecules were found to better targets for osteoarthritis treatment. Inhibition of these two molecules reduced degradation and improved formation of cartilage. Lastly, the biomarkers of joint degradation were measured in a clinical study testing a potential novel rheumatoid arthritis treatment, fostamatinib. Fostamatinib was also tested in tissue cultures of bone, cartilage and synovial degradation, with measurements of the same bi-omarkers as in the clinical study. The effect of fostamatinib on the biomarkers was translated from clinical study to the tissue cultures. Indicating that the structural effect of potential treatments measured by degradation biomarkers can be translated from clinical studies to laboratory studies and vice versa. In conclusion, the tissue culture models together with the tissue degradation biomarkers provided a translational tool, which may benefit drug development of structure-modifying treatments for osteoar-thritis and rheumatoid arthritis.