Negative Regulators of JAK/STAT Signaling in Rheumatoid Arthritis and Osteoarthritis.

Charles Malemud

doi:10.3390/ijms18030484

Abstract

Elevated levels of pro-inflammatory cytokines are generally thought to be responsible for driving the progression of synovial joint inflammation in rheumatoid arthritis (RA) and osteoarthritis (OA). These cytokines activate several signal transduction pathways, including the Janus kinase/Signal Transducers and Activators of Transcription (JAK/STAT), Stress-Activated/Mitogen-Activated Protein Kinase (SAPK/MAPK) and phosphatidylinositol-3-kinase/Akt/mechanistic target of rapamycin (PI3K/Akt/mTOR) pathways which regulate numerous cellular responses. However, cytokine gene expression, matrix metalloproteinase gene expression and aberrant immune cell and synoviocyte survival via reduced apoptosis are most critical in the context of inflammation characteristic of RA and OA. Negative regulation of JAK/STAT signaling is controlled by Suppressor of Cytokine Signaling (SOCS) proteins. SOCS is produced at lower levels in RA and OA. In addition, gaining further insight into the role played in RA and OA pathology by the inhibitors of the apoptosis protein family, cellular inhibitor of apoptosis protein-1, -2 (c-IAP1, c-IAP2), X (cross)-linked inhibitor of apoptosis protein (XIAP), protein inhibitor of activated STAT (PIAS), and survivin (human) as well as SOCS appears to be a worthy endeavor going forward.

Highlights

Numerous pro-inflammatory cytokines including, interleukin-1β (IL-1β), IL-2, IL-3, IL-6, IL-7, IL-8, IL-12/23, IL-17, IL-18, IL-19/IL-20, IL-32, IL-35, tumor necrosis factor-α (TNF-α), interferon-α/γ (IFNα/γ) and oncostatin M (OSM) are prominently elevated in rheumatoid arthritis (RA) where they are involved in immune-mediated inflammation characteristic of this autoimmune disease [1,2,3,4,5]
Suppressor of Cytokine Signaling (SOCS)-2 and CIS-1 mRNA levels were reduced six-fold and three-fold, respectively, when chondrocytes were incubated with IL-1β and OSM, in combination with TNF-α, suggesting that the pro-inflammatory cytokines implicated in OA progression and altered cartilage extracellular matrix structure were likely associated with activated JAK/STAT via the reduced expression of the SOCS-2 and CIS-1 genes
One current state of research in this area focuses on unraveling the molecular mechanisms which regulate aberrant cell survival, apoptosis and matrix metalloproteinase gene activity in these conditions

Summary

Introduction

Numerous pro-inflammatory cytokines including, interleukin-1β (IL-1β), IL-2, IL-3, IL-6, IL-7, IL-8, IL-12/23, IL-17, IL-18, IL-19/IL-20, IL-32, IL-35, tumor necrosis factor-α (TNF-α), interferon-α/γ (IFNα/γ) and oncostatin M (OSM) are prominently elevated in rheumatoid arthritis (RA) where they are involved in immune-mediated inflammation characteristic of this autoimmune disease [1,2,3,4,5]. Three of these cytokines in particular, namely IL-1β and IL-6 and TNF-α, were found at elevated levels in patients diagnosed with osteoarthritis (OA) [6,7,8]. This refers to the impact of two main endogenous negative regulators of JAK/STAT, notably Suppressor of Cytokine Signaling (SOCS) [30] and cellular Inhibitor of Apoptosis Proteins (c-IAPs), including the Protein Inhibitor of Activated STAT (PIAS) [12,31]

Mechanisms Attributed to Activity of Suppressor of Cytokine Signaling

Suppressor of Cytokine Signaling and Rheumatoid Arthritis

Suppressor of Cytokine Signaling and and Osteoarthritis

Conclusions and Future Perspectives