Abstract
Rheumatoid arthritis (RA) is a chronic autoimmune disease that primarily attacks synovial joints. Despite the advances in diagnosis and treatment of RA, novel molecular targets are still needed to improve the accuracy of diagnosis and the therapeutic outcomes. Here, we present a systems approach that can effectively 1) identify core RA-associated genes (RAGs), 2) reconstruct RA-perturbed networks, and 3) select potential targets for diagnosis and treatments of RA. By integrating multiple gene expression datasets previously reported, we first identified 983 core RAGs that show RA dominant differential expression, compared to osteoarthritis (OA), in the multiple datasets. Using the core RAGs, we then reconstructed RA-perturbed networks that delineate key RA associated cellular processes and transcriptional regulation. The networks revealed that synovial fibroblasts play major roles in defining RA-perturbed processes, anti-TNF-α therapy restored many RA-perturbed processes, and 19 transcription factors (TFs) have major contribution to deregulation of the core RAGs in the RA-perturbed networks. Finally, we selected a list of potential molecular targets that can act as metrics or modulators of the RA-perturbed networks. Therefore, these network models identify a panel of potential targets that will serve as an important resource for the discovery of therapeutic targets and diagnostic markers, as well as providing novel insights into RA pathogenesis.
Highlights
Rheumatoid Arthritis (RA) is a chronic autoimmune disease that primarily attacks synovial joints
Among 30 different differential expression pattern (DEPs) clusters of the genes resulted from the negative matrix factorization (NMF) analysis, we selected seven major Differential Expression Patterns (DEPs) clusters (P,0.05; see Materials and Methods) and identified the genes significantly showing each DEP (P,0.05) as RA-associated genes (RAGs) (Figures 1A and 1B)
The shared RAGs indicate that both RA and OA share certain pathological processes, consistent with previous findings that both diseases show common characteristics related to chronic inflammatory arthritis
Summary
Rheumatoid Arthritis (RA) is a chronic autoimmune disease that primarily attacks synovial joints. In the RA joints, various inflammatory cells, including innate immune cells (e.g. mast cells, macrophages, dendritic cells, and NK cells), adaptive immune cells (T- and B-cells), and fibroblast-like synoviocytes (FLS), are activated. These cells interact with each other via an array of cytokines and/or cell-to-cell contacts, leading to prolonged inflammation, abnormal proliferation of FLS, and the destruction of cartilage and bone [1,2,3]. Rheumatoid factor and anti-CCP antibody, well-known diagnostic markers for RA, represent B-cell hyperactivity to selfantigens, but are limited in reflecting the multi-cellular communication networks occurring in the RA joints
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