Cartilage damage is a key event in several inflammatory musculoskeletal diseases (IMDs), particularly in rheumatoid arthritis (RA). We have shown previously that in RA, early cartilage damage is a key triggering factor for mesenchymal fibroblast-like synoviocytes (FLS) to acquire their disease-specific, aggressive and migratory phenotype. Generating high resolution class I epigenomes of FLS from human RA patients and from animal models of the disease in frame of the BMBF- funded National Epigenome Consortium (DEEP), we have recently identified a panel of candidate genes such as Lasp1 that are epigenetically altered and in- volved in the transformation of FLS in RA. However, aside from a gen- eral understanding that cartilage degradation products can stimulate neighbouring cells, the mechanisms by which cartilage damage in the context of other alterations such as of the immune system triggers epi- genetic changes and may exert disease-specific effects in IMDs remain unclear. Interestingly, our own data from degenerative joint diseases suggest that cartilage damage not only leads to the release of structural proteins and their fragments but far more importantly, also results in the release of chemokines and growth factors that are bound in healthy ar- ticular cartilage and normally serve as homeostatic factors for chondro- cytes. Based on these data, we want to investigate how in chronic auto- immune inflammation, soluble factors as released from cartilage regulate the epigenetic profile of mesenchymal cells and contribute to the devel- opment of an autonomously aggressive phenotype. We want to follow the hypothesis that soluble factors as released at cartilage damage in the context of a ‘second hit’, as for instance the lack of regulatory immune mechanisms leads to the epigenetic imprinting of signals in mesenchy- mal cells and, thus, contributes to the switch from acute to chronic IMDs. We propose that inhibition of these signals affects the chronicity of IMDs and promotes the resolution of inflammatory tissue damage and facilitates regenerative attempts.