Tumour-necrosis-factor-stimulated gene 6 encodes a protein (TSG-6) that is absent in most healthy adult tissue but is synthesized in response to inflammatory mediators and during inflammation-like processes such as ovulation. Extracellular matrix (ECM) remodelling is a notable feature of sites of TSG-6 expression, and TSG-6 has anti-inflammatory and chondroprotective effects in models of inflammation and arthritis. In a Commentary on p. 1863,Caroline Milner and Anthony Day review our understanding of the properties of this interesting protein. TSG-6 is a secreted protein and contains a Link module – a domain present in many proteins that bind to the ECM component hyaluronan. It interacts with the serine protease inhibitor IαI, which like TSG-6 is a hyaluronanbinding protein. It binds to two other matrix components: chondroitin 4-sulphate and aggregan. The interaction with IαI appears to modulate formation of IαI-hyaluronan complexes in the ECM and, independently, enhance the anti-plasmin activity of IαI– both...

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