Up-regulation and differential expression of the hyaluronan-binding protein TSG-6 in cartilage and synovium in rheumatoid arthritis and osteoarthritis.

OBJECTIVE: TSG-6 [the product of tumor necrosis factor (TNF)-stimulated gene-6] is a hyaluronan-binding protein that is present in the synovial fluids of arthritis patients and is secreted by cells of articular joints (e.g. chondrocytes and synoviocytes). This study examines the pattern of TSG-6 expression in normal and diseased cartilage and synovium using immunohistochemical techniques. DESIGN: A polyclonal antibody was raised against recombinant Link module from human TSG-6 and used to detect the protein in tissue sections taken from osteoarthritis (OA) and rheumatoid arthritis (RA) patients and controls. RESULTS: There was no TSG-6 detected in normal tissues. In all OA synovium there was intense TSG-6 expression throughout the intimal layer, whereas in RA staining in this region was generally less pronounced and was absent at the synovial surface in tissues exhibiting significant inflammation. In RA TSG-6 was also expressed by infiltrating leukocytes and by cells at the cartilage-synovium pannus junction. TSG-6 immunoreactivity was present in the tunica intima of blood vessels in OA subintima, being particularly noticeable in the thickened smooth muscle of inflamed vessel walls, but was mostly confined to the lumen of the vessel in RA. In cartilage the majority of chondrocytes expressed TSG-6 in both OA and RA, usually with extensive staining in the surrounding matrix. CONCLUSION: TSG-6 is present within synovium and cartilage of arthritic joints, but not normal controls, and is synthesized by the resident cells. The pattern of TSG-6 expression is consistent with its proposed roles in extracellular matrix (ECM) remodeling and cellular proliferation.

TSG-6 interacts with hyaluronan and aggrecan in a pH-dependent manner via a common functional element: implications for its regulation in inflamed cartilage.

Cartilage matrix is stabilised by the interactions of proteins with hyaluronan (HA). We compare the pH dependences of HA binding by aggrecan, link protein and TSG-6. Aggrecan and link protein exhibit maximal binding across a wide pH range (6.0-8.0). TSG-6, a protein that is only produced during inflammation, binds maximally at about pH 6.0 but shows a dramatic loss of function with increasing pH. TSG-6 also interacts with aggrecan, with a similar pH dependence, and this can be inhibited by HA. Thus, a common binding surface on TSG-6 may be involved in HA and aggrecan binding. We propose that TSG-6 is involved in matrix dissociation and that this is regulated by pH gradients in cartilage.