A Role for Soluble IL-6 Receptor in Osteoarthritis

Abstract

Interleukin-6 (IL-6) is one of several pro-inflammatory cytokines present at elevated levels in the synovial fluid of individuals with confirmed clinical diagnosis of rheumatoid arthritis (RA) and osteoarthritis (OA). The mechanism of action of IL-6 was shown to involve its capacity to interact with a membrane-bound IL-6 receptor (mIL-6Rα), also known as the “classical” IL-6 pathway, or through its interaction with a soluble IL-6 receptor (sIL-6R) termed the “trans-signaling” pathway. Activation of downstream signaling is transduced via these IL-6 receptors and principally involves the Janus Kinase/Signal Transduction and Activators of Transcription (JAK/STAT) signaling pathway that is further regulated by glycoprotein-130 (gp130) interacting with the IL-6/mIL-6R complex. Phosphorylation of STAT proteins via JAK activation facilitates STAT proteins to act as transcription factors in inflammation. However, the biological function(s) of the sIL-6R in human chondrocytes requires further elucidation, although we previously showed that exogenous sIL-6R significantly suppressed the synthesis of neutrophil gelatinase-associated lipocalin (NGAL) in the immortalized line of human chondrocytes, C28/I2. NGAL was shown to regulate the activity of matrix metalloproteinase-9 (MMP-9), whose activity is crucial in OA for the destruction of articular cartilage. The “shedding” of sIL-6R from the plasma membrane is carried out by a family of enzymes known as A Distintegrin and Metalloproteinase (ADAM), which are also elevated in OA. In this paper, we have systematically reviewed the role played by IL-6 in OA. We have proposed that sIL-6R may be an important target for future drug development in OA by ameliorating cartilage extracellular protein degradation.

Anti-Inflammatory Activity of Exopolysaccharides from Phormidium sp. ETS05, the Most Abundant Cyanobacterium of the Therapeutic Euganean Thermal Muds, Using the Zebrafish Model

“…Interestingly, the inflammatory markers analyzed in this work, and in particular il6, il8, and mmp13, were found to be upregulated also in osteoarthritis (OA) and rheumatoid arthritis (RA), the two most common types of arthritis [74][75][76][77][78], providing a clue to the possible mechanisms used by these molecules against these painful pathologies.…”

Altered Wnt and NF-<i>κ</i>B Signaling in Facet Joint Osteoarthritis: Insights from RNA Deep Sequencing

“…Osteoarthritis has been recognized as an inflammatory disease since inflammation is implicated in the osteoarthritis pain process and cartilage degradation process (Berenbaum 2013;Rahmati et al 2016). Many inflammatory cytokines and inflammatory mediators, such as interleukin-1, interleukin-6, and tumor necrosis factor, were involved in the pathophysiology of osteoarthritis (Fernandes et al 2002;Akeson and Malemud 2017;Suyasa et al 2017). Anti-inflammatory proteins were also demonstrated to exhibit a favorable role in the treatment of osteoarthritis (van Drumpt et al 2016;Hix et al 2017;Kon et al 2018).…”

Zac1 regulates IL-11 expression in osteoarthritis

“…IL-6 and its family of proteins, including oncostatin M, are among the most prominently elevated cytokines in the OA inflammatory response [ 62 ]. Many studies have correlated of IL-6 levels in synovial fluid with cartilage pathology and associated outcomes in knee OA.…”