Defining Novel Targets for Intervention in Rheumatoid Arthritis: An Overview

Abstract

Many and sometimes disparate immune and non-immune-mediated events contribute to the pathogenesis and progression of rheumatoid arthritis (RA). Despite recent advances in the development and implementation of diseasemodifying anti-rheumatic drugs and biological response modifiers for the treatment of RA, it remains vital that additional RA targets suitable for RA intervention be identified. Such novel targets for RA intervention would include, noninterleukin-1 (non-IL-1)/non-tumor necrosis factor-/non-IL-6 pro-inflammatory cytokines, growth factors that regulate angiogenesis as well as those required for synovial joint tissue repair. Proteins that are integral to the modulation of Tlymphocyte, B-lymphocyte, monocyte activity and synovial tissue apoptosis as well as complement, chemokines, adhesion molecules must also be considered. Because articular cartilage destruction and subchondral bone erosions are hallmarks of RA pathology, agents with the capability of modifying matrix metalloproteinases, tissue inhibitor of metalloproteinases and the family of enzyme proteins referred to as a disintegrin and metalloproteinases (ADAMs) or ADAMs with a thrombospondin motif (ADAMTS) as well as factors that regulate osteoclastogenesis and osteoclast activity such as receptor activator of nuclear factor-B ligand (RANKL) should also be pursued.

The role of the JAK/STAT signal pathway in rheumatoid arthritis

“…[8][9][10] In addition, the significantly elevated levels of proinflammatory cytokines, exemplified, by tumor necrosis factor-α (TNF-α), interleukin (IL)-1ß, IL-6, IL-7, IL-8, IL-12/IL-23, IL-15, IL-17, IL-18, IL-32, and, interferon-γ (IFNγ) produced by various cells, together with growth factors, such as fibroblast growth factor-2 (FGF-2) and vascular endothelial growth factor, the latter produced mainly by synovial-like fibroblasts and macrophages, have been shown to be crucial for RA to clinically progress whereby the destruction of articular cartilage and erosion of subchondral bone are the principal events that result in synovial joint failure. 9,[11][12][13] Thus, the overall changes occurring in RA synovial joints in response to these various factors, including suppression of cartilage-derived extracellular matrix production, 14 an elevated frequency of apoptotic chondrocytes, 15 synovial tissue 'apoptosis resistance', 16 and an increased level of matrix metalloproteinase (MMP) gene expression 17 as well as that class of enzymes, termed, a disintegrin and metalloproteinase (ADAM) 18 gene expression are all critical components of the RA process.…”

The Small Molecule Inhibitor of Protein Kinase Revolution for the Treatment of Rheumatoid Arthritis

“…Over the past 8 years or so, we have extensively detailed the genesis of interest in, and the extent to which, kinase activity of mitogen-activated protein kinases (MAPK) and the phosphatidylinositide-3-kinase/AKT/mammalian target of rapamycin (mTOR) (PI3K/AKT/mTOR) pathways influence MMP gene expression and cell survival, respectively [37][38][39][40][41]. We and others have also focused attention on the Janus Kinase/Signal Transducers and Activators of Transcription (JAK/STAT) pathway which was identified and targeted for drug development in RA because JAK/STAT signaling was found to play a major role in RA by promoting proinflammatory cytokine gene expression and abnormal cell survival [42][43][44][45][46][47][48].…”

Vaccine development for rheumatoid arthritis

“…From a molecular and pathophysiologic perspective the destruction of the RA synovial joints is further facilitated by aberrant signal transduction [16], by up-regulation of pro-inflammatory cytokine gene expression [17], and by increased chemokine and adhesion protein synthesis [18,19]. The increase in pro-inflammatory cytokines, exemplified by tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and IL-6 gene expression causes elevated matrix metalloproteinase (MMP) synthesis to occur which, in RA, is typically responsible for ECM protein degradation in articular cartilage [18,20].…”