The Role of Interleukin-6 in osteoarthritic Pain and Homeostasis of Chondrocytes

• Applicants: Dr. Annett Eitner; Professor Dr. Hans-Georg Schaible
• Subject Area: Orthopaedics, Traumatology, Reconstructive Surgery
• Term: since 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 450764314

Osteoarthritis is the most frequent cause of pain in the knee and the hip joint. Many patients suffer for years from increasing pain and functional restrictions, until the afflicted joint is finally replaced by an artificial joint. Currently there are no disease modifying drugs available, and the analgesic potential of cyclooxygenase inhibitors is in the long-term not sufficient. Because of the growing importance of osteoarthritis, new approaches are required. In our research on pain mechanisms in advanced knee osteoarthritis, we found that the pain intensity is correlated with the severity of synovitis. We found a pronounced synovitis in particular in obese diabetic patients, and their pain intensity was strongly correlated with the concentration of interleukin-6 in the synovial fluid. By recording from joint nociceptors in the rat, we showed that interleukin-6 significantly and persistently sensitizes nociceptive C-fibres of the joint for mechanical stimuli. Since interleukin-6 is also an important pathogenic factor in the development of osteoarthritis, we put forward the hypothesis that the blockade of interleukin-6 effects may be a promising approach for efficient pain therapy in osteoarthritis. For that purpose it is necessary to better understand the cellular nociceptive mechanisms of interleukin-6 and to exclude at the same time that the neutralization of interleukin-6 has negative effects on chondrocytes. Interleukin-6 acts either on IL-6 receptors in the cell membrane, or through the so-called trans-signalling. In the latter a complex is formed by interleukin-6 and a soluble IL-6 receptor (sIL-6R) which can also have an effect on cells witout a membrane-bound IL-6 receptor. The first aim is to explore in rat neurons through which cellular mechanisms interleukin-6 contributes to pain. Are TRP ion channels (in particular mechanosensitive TRPV4 channels) and prostaglandins involved? Is interleukin-6 a final common cytokine pathway of pain producing proinflammatory mechanisms? Is interleukin-6 able to damage nerve fibers? The second aim is to explore whether human chondrocytes, obtained from patients undergoing arthroplasty of the knee joint, release by themselves interleukin-6 and the soluble IL-6 receptor, and how interleukin-6 acts on chondrocytes. Does interleukin-6 influence, directly or by trans-signalling, positively or negatively, important homeostatic functions in chondrocytes in the ATP generation in mitochondria and in the signalling of mechanical load by mechanosensitive TRPV4 ion channels? From these data we expect insights whether the blockade of effects of interleukin-6 is a potential approach for the therapy of osteoarthritis pain which is independent on prostaglandins and which does not further damage the cartilage upon neutralization.

• DFG Programme: Research Grants