Epigenetic regulation of apoptosis-resistance of synovial
Epigenetic regulation of apoptosis-resistance of synovial fibroblasts from patients with RA
Pajak A, Gay S, Neidhart M, Distler O, Jüngel A
Rheumatoid arthritis (RA) is a systemic autoimmune disease, which symmetrically affects multiple joints; worldwide 0.5 -1% of the population is affected. Early disability together with high costs of the long-term treatment regime result in high socioeconomic impact. Although in the last years, uses of biologics resulted in considerable advances in the treatment improving patient’s outcomes. Still around one third of patients respond insufficiently or not at all to therapies, underscoring the need for new treatment strategies. Traditionally, fibroblasts have been considered to contribute to the structural integrity of tissues rather than playing a dynamic role in physiological or pathological processes. Recent reports suggest that synovial fibroblasts influence the synovial pathotypes and non-response to RA therapy. They contribute to the local production of cytokines, small molecule mediators of inflammation, and proteolytic enzymes that degrade the extracellular matrix. It is thought that the synovial tissue becomes hyperplastic due to their resistance to apoptosis. Of particular interest, the Fas receptor (FasR) - Fas ligand (FasL) apoptotic pathway appears altered in RA. Long non-coding RNAs (lncRNAs) are emerging as key regulators of gene expression. Their role in disease, however, is still poorly understood. Our preliminary data demonstrate that a specific lncRNA regulates Fas ligand-induced apoptosis under inflammatory conditions.
This project will demonstrate the intricate involvement of lncRNAs in the pathogenic-relevant signaling pathway of apoptosis-resistance that might be used for novel epigenetic-based therapeutic strategies to complement the hitherto therapeutic approaches.
Astrid Jüngel is a senior scientist at the Centre of Experimental Rheumatology, University Hospital Zurich. Her interests are the epigenetic modifications in synovial fibroblasts of RA.
- Epigenetics (RNA regulated gene expression)
- Synovial fibroblasts