A cytokine protein-protein interaction network for identifying key molecules in rheumatoid arthritis.

Venugopal Panga,Srivatsan Raghunathan,Hua Zhou

doi:10.1371/journal.pone.0199530

Abstract

Rheumatoid arthritis (RA) is a chronic inflammatory disease of the synovial joints. Though the current RA therapeutics such as disease-modifying antirheumatic drugs (DMARDs), nonsteroidal anti-inflammatory drugs (NSAIDs) and biologics can halt the progression of the disease, none of these would either dramatically reduce or cure RA. So, the identification of potential therapeutic targets and new therapies for RA are active areas of research. Several studies have discovered the involvement of cytokines in the pathogenesis of this disease. These cytokines induce signal transduction pathways in RA synovial fibroblasts (RASF). These pathways share many signal transducers and their interacting proteins, resulting in the formation of a signaling network. In order to understand the involvement of this network in RA pathogenesis, it is essential to identify the key transducers and their interacting proteins that are part of this network. In this study, based on a detailed literature survey, we have identified a list of 12 cytokines that induce signal transduction pathways in RASF. For these cytokines, we have built a signaling network using the protein-protein interaction (PPI) data that was obtained from public repositories such as HPRD, BioGRID, MINT, IntAct and STRING. By combining the network centrality measures with the gene expression data from the RA related microarrays that are available in the open source Gene Expression Omnibus (GEO) database, we have identified 24 key proteins of this signaling network. Two of these 24 are already drug targets for RA, and of the remaining, 12 have direct PPI links to some of the current drug targets of RA. Therefore, these key proteins seem to be crucial in the pathogenesis of RA and hence might be treated as potential drug targets.

Highlights

Rheumatoid arthritis (RA) is a debilitating chronic inflammatory synovial joint disease that affects about 1% of the world’s population [1]
These cytokines stimulate the RA synovial fibroblasts (RASF) and activate their respective transcription factors. We considered these cytokines as the sources and their transcription factors as the targets in synovial PPI network’ (SPPIN)
Even though the number of cytokines considered in this study is low, they are reliable in the sense that they stimulate RASF and induce signal transduction pathways leading to the activation of their respective transcription factors

Summary

Introduction

RA is a debilitating chronic inflammatory synovial joint disease that affects about 1% of the world’s population [1]. The disease usually affects the small joints of the hands and feet. The etiology of the disease is unknown. The chronic inflammation causes invasion of synovial membrane toward articular bone which results in the formation of a layer of granulation tissue, called pannus.

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