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TSG-6 is an inflammation-induced protein that is produced at pathological sites, including arthritic joints. In animal models of arthritis, TSG-6 protects against joint damage; this has been attributed to its inhibitory effects on neutrophil migration and plasmin activity. Here we investigated whether TSG-6 can directly influence bone erosion. Our data reveal that TSG-6 inhibits RANKL-induced osteoclast differentiation/activation from human and murine precursor cells, where elevated dentine erosion by osteoclasts derived from TSG-6(-/-) mice is consistent with the very severe arthritis seen in these animals. However, the long bones from unchallenged TSG-6(-/-) mice were found to have higher trabecular mass than controls, suggesting that in the absence of inflammation TSG-6 has a role in bone homeostasis; we have detected expression of the TSG-6 protein in the bone marrow of unchallenged wild type mice. Furthermore, we have observed that TSG-6 can inhibit bone morphogenetic protein-2 (BMP-2)-mediated osteoblast differentiation. Interaction analysis revealed that TSG-6 binds directly to RANKL and to BMP-2 (as well as other osteogenic BMPs but not BMP-3) via composite surfaces involving its Link and CUB modules. Consistent with this, the full-length protein is required for maximal inhibition of osteoblast differentiation and osteoclast activation, although the isolated Link module retains significant activity in the latter case. We hypothesize that TSG-6 has dual roles in bone remodeling; one protective, where it inhibits RANKL-induced bone erosion in inflammatory diseases such as arthritis, and the other homeostatic, where its interactions with BMP-2 and RANKL help to balance mineralization by osteoblasts and bone resorption by osteoclasts.

Original publication

DOI

10.1074/jbc.m802138200

Type

Journal article

Journal

The Journal of biological chemistry

Publication Date

09/2008

Volume

283

Pages

25952 - 25962

Addresses

Nuffield Department of Orthopaedic Surgery, Botnar Research Centre, University of Oxford, Windmill Rd., Headington, Oxford OX3 7LD, United Kingdom.

Keywords

NIH 3T3 Cells, Osteoclasts, Osteoblasts, Animals, Mice, Transgenic, Humans, Mice, Bone Resorption, Transforming Growth Factor beta, Cell Adhesion Molecules, Bone Morphogenetic Proteins, Recombinant Proteins, Bone Remodeling, Kinetics, RANK Ligand, Bone Morphogenetic Protein 2