Importance of IL-6 trans-signaling and high autocrine IL-6 production in human osteoarthritic chondrocyte metabolism

Objective: Neutralization of Interleukin (IL) -6 -signaling by antibodies is considered a promising tool for the treatment of osteoarthritis (OA). To gain further insight into this potential treatment, this study investigated the effects of IL -6 -signaling and IL -6 neutralization on chondrocyte metabolism and the release of IL -6signaling -related mediators by human chondrocytes. Design: Chondrocytes were collected from 49 patients with advanced knee/hip OA or femoral neck fracture. Isolated chondrocytes were stimulated with different mediators to analyze the release of IL -6, soluble IL -6 receptor (sIL-6R) and soluble gp130 (sgp130). The effect of IL -6 and IL-6/sIL-6R complex as well as neutralization of IL -6 -signaling on the metabolism was analyzed. Results: OA chondrocytes showed high basal IL -6 production and release, which was strongly negatively correlated with the production of cartilage -matrix -proteins. Chondrocytes produced and released sIL-6R and sgp130. The IL-6/sIL-6R complex significantly increased nitric oxide, prostaglandin E 2 and matrix metalloproteinase 1 production, decreased Pro -Collagen Type II and mitochondrial ATP production, and increased glycolysis in OA chondrocytes. Neutralization of IL -6 -signaling by antibodies did not significantly affect the metabolism of OA chondrocytes, but blocking of glycoprotein 130 (gp130)-signaling by SC144 significantly reduced the basal IL -6 release. Conclusion: Although IL -6 trans -signaling induced by IL-6/sIL-6R complex negatively affects OA chondrocytes, antibodies against IL -6 or IL -6R did not affect chondrocyte metabolism. Since inhibition of gp130-signaling reduced the enhanced basal release of IL -6, interfering with gp130-signaling may ameliorate OA progression because high cellular release of IL -6 correlates with reduced production of cartilage -matrix -proteins. (c) 2024 The Author(s). Published by Elsevier Ltd on behalf of Osteoarthritis Research Society International. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).