sgp130Fc alleviates cartilage degeneration and knee osteoarthritis by inhibiting IL-6 trans-signaling pathway

Abstract

Background

Interleukin-6 (IL-6) trans-signaling plays a pivotal role in the pathogenesis and progression of osteoarthritis (OA), contributing to chronic intra-articular inflammation and cartilage degradation. Soluble gp130-Fc (sgp130Fc) is a selective inhibitor of IL-6 trans-signaling that spares classical signaling. This study aimed to elucidate the role of IL-6 trans-signaling in knee OA and evaluate the therapeutic potential of sgp130Fc.

Methods

Synovial fluid from OA patients at different disease stages was analyzed for IL-6, soluble IL-6 receptor (sIL-6R), and sgp130 levels by ELISA. Primary rat chondrocytes were treated with Hyper-IL-6 to activate IL-6 trans-signaling and co-treated with sgp130Fc to assess cell viability, gene expression, and lipid metabolism alterations. A rat OA model was established via the Hulth method, followed by intra-articular administration of sgp130Fc. Histological, immunohistochemical, and lipidomic analyses were performed to evaluate cartilage integrity and inflammatory responses.

Results

Levels of IL-6, sIL-6R, and sgp130 in synovial fluid increased with OA progression. Hyper-IL-6 impaired chondrocyte viability, activated JAK1-STAT3 signaling, promoted inflammatory and catabolic gene expression, and disrupted lipid metabolism, all of which were reversed by sgp130Fc treatment. In vivo, sgp130Fc injections alleviated cartilage degradation, reduced synovitis, suppressed inflammatory mediators, and restored lipid homeostasis.

Conclusions

Targeted inhibition of IL-6 trans-signaling with sgp130Fc effectively mitigates cartilage degeneration and inflammation in OA, highlighting its potential as a novel disease-modifying therapeutic strategy for knee osteoarthritis.