Abstract
Osteoarthritis (OA) is a common joint disease affecting mainly the elderly population. In younger people it can be caused by joint trauma or congenital afflictions. OA is characterized by cartilage damage, synovial fibrosis and osteophyte formation. TGF-ß is a growth factor that is a potent inducer of cartilage extracellular matrix production and is therefore a potential tool to enhance repair of damaged cartilage. Deficiencies in the TGF-ß signaling pathway lead to OA-like phenotypes. Thus during OA TGF-ß function might be compromised. We found that with age, and in experimental OA models, the TGF-ß signaling cascade was compromised. As age is a risk factor for OA, this reduced TGF-ß signaling might be at the root of cartilage damage during OA. To investigate if the reduced TGF-ß activity could be compensated, we exposed damaged cartilage to TGF-ß. This resulted in enhanced cartilage repair. However, TGF-ß was shown to induce synovial fibrosis and osteophyte formation. Therefore, it is crucial to separate the beneficial effects of TGF-ß on cartilage from the unwanted side effects. By local inhibition of TGF-ß in the synovium, during TGF-ß over expression in murine knee joints, we were able to prevent synovial fibrosis, while maintaining the beneficial effect of TGF-ß on cartilage. However, as we used adenoviruses to achieve this, this is not applicable in the clinic. It would be beneficial to identify specific secondary mediators for negative side effects induced by TGF-ß. As secondary mediators, CTGF, for synovial fibrosis, and BMP-2, for osteophyte formation, were identified. Their influence on cartilage, synovium and osteophyte formation was investigated and described in this thesis. Unfortunately they did not dominate the side effects enough to serve as targets for therapeutic intervention. However, our studies have contributed to better understanding of the processes underlying TGF-ß effects and the role of TGF-ß in OA pathogenesis.
