Osteoarthritis and Cartilage
Osteoarthritis and Cartilage
5 years ago

TSG-6 – a Double-Edged Sword for Osteoarthritis

To explore mechanisms underlying the association of TSG-6 with osteoarthritis (OA) progression. Methods TSG-6-mediated heavy chain (HC) transfer (TSG-6 activity) and its association with inflammatory mediators were quantified in knee OA (n=25) synovial fluids. Paired intact and damaged cartilages from the same individuals (20 tibial and 12 meniscal) were analyzed by qRT-PCR and immunohistochemistry (IHC) for gene and protein expression of TSG-6 and components of IαI (necessary for TSG-6 activity), and for TSG-6 activity +/- spiked in IαI. Primary chondrocyte culture (n=5) +/- IL1ß or TNFα were also evaluated for gene expression. The effects of TSG-6 activity on cartilage extracellular matrix assembly were explored using quantitative hyaluronan (HA)-aggregan binding assays. Results TSG-6 activity was significantly associated (R>0.683, p<0.0002) with inflammatory mediators including TIMP-1, A2M, MMP3, VEGF, VCAM-1, ICAM-1 and IL-6. Although TSG-6 protein and mRNA were highly expressed in damaged articular and meniscal cartilage and cytokine-treated chondrocytes, there was little or no cartilage expression of components of the IαI complex (containing HC1). By IHC, TSG-6 was present throughout lesioned cartilage but HC1 only at lesioned surfaces. TSG-6 impaired HA-aggrecan assembly, but TSG-6 mediated HA-HC formation reduced this negative effect. Conclusion TSG-6 activity is a global inflammatory biomarker in knee OA synovial fluid. IαI, supplied from outside cartilage, only penetrates to the surface, restricting TSG-6 activity (HC transfer) to this region. Therefore, unopposed TSG-6 in intermediate and deep regions of OA cartilage could possibly block matrix assembly, leading to futile synthesis and account for increased risk of OA progression.

Publisher URL: www.sciencedirect.com/science

DOI: S106345841731302X

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