Fibroblasts play a dominant role in the pathophysiology of inflammatory musculosceletal diseases (IMDs). In rheumatoid arthritis (RA), fibroblast-like synovio-cytes (FLS), particularly in the lining layer of chronically inflamed joints exert a stable, aggressive phenotype, which is different from that in acutely inflamed joints and also from that in deeper parts of the synovium. There is evidence that the local microenvironment is a driving factor for pathogenic fibroblast ef- fector functions and that these may differ not only between different IMDs but also within a given mesenchymal compartment, e.g. a joint. Recently, we and others showed that epigenetic changes are important for the phenotypic switch of FLS and that alterations of the microenvironment or medication can alter this phenotype. Here, we want to delineate (i) how the microenvironment instructs the aggressive phenotype in FLS and (ii) if and how this can be modulated by altering the expression of relevant micro RNAs (miRs). To dissect relevant instructive signals, we will, in cooperation with our partners, focus on three major factors: the vasculature, the extracellular matrix (ECM) and the adaptive im- mune system. We will use a combination of hypothesis-driven approaches based on our existing data along with novel screening strategies including mass cytometry-based single cell analysis to unravel the characteristics of aggressively transformed lining layer FLS in RA in comparison with other IMDs. In a preclinical translational approach, we will delineate how overexpression rele- vant of miRs or their downregulation by antagomirs can revert the aggressive phenotype of FLS both in vitro and animal models of IMDs, including G6PI-induced arthritis and the SCID mouse model.