Role of synovial lining fibroblasts in inflammatory arthritis

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Project Summary Fibroblast-like synoviocytes (FLS) are cells, lining of the joint surfaces. They play a critical role in the pathology of Inflammatory Joint Diseases (IJD), such as rheumatoid arthritis, psoriatic arthritis and juvenile idiopathic arthritis. Under chronic inflammation, FLS undergo epigenetic remodeling and are transformed into aggressive cancer-like cells, which evade apoptosis, proliferate, and produce catabolic factors that degrade the articular cartilage and subchondral bone. Once, transformed, the FLS are known to retain their aggressive properties in spite of removing them from the inflammatory microenvironment. Epigenetic remodeling is suggested as the underlying cause. In this proposal, we will focus on a specific subtype of FLS that are located in synovial lining (L-FLS). Our overarching hypothesis is that the L-FLS function as disease-initiating stem-like cells. We propose that they act as the initiators and perpetuators of joint degeneration by giving rise to other aggressive FLS subpopulations and by acquiring long-term epigenetic memory that is implicated in failure to remission. We will test this hypothesis by determining if the L-FLS possess characteristics, such as, differentiation into another aggressive subpopulation and retain their epigenetic changes even after resolution of inflammation. In Aim 1 we will use lineage tracing to identify the L-FLS can give rise to other pathological subtypes. Under Aim 2 we will investigate if intrinsic epigenetic in L-FLS are irreversible and are responsible for disease persistence. Successful completion of this proposal will establish L-FLS as IJD-driving cells, which possess the ability to initiate catabolic changes in the joint as well as confer persistence of the disease phenotype. We anticipate that the L-FLS will be identified as ideal targets to prevent therapeutic resistance and recurrence of symptoms.