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J. Biol. Chem., Vol. 283, Issue 38, 25952-25962, September 19, 2008

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TSG-6 Regulates Bone Remodeling through Inhibition of Osteoblastogenesis and Osteoclast Activation^*

David J. Mahoney, Katalin Mikecz^¶, Tariq Ali^||, Guillaume Mabilleau, Dafna Benayahu^**, Anna Plaas, Caroline M. Milner^||3, Anthony J. Day^||1, and Afsaneh Sabokbar²

From the Nuffield Department of Orthopaedic Surgery, Botnar Research Centre, University of Oxford, Windmill Rd., Headington, Oxford OX3 7LD, United Kingdom, MRC Immunochemistry Unit, Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, United Kingdom, ^¶Department of Orthopedic Surgery, Rush University Medical Center, Chicago, Illinois 60612, ^||Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, University of Manchester, Michael Smith Bldg., Oxford Rd., Manchester M13 9PT, United Kingdom, ^**Department of Cell and Developmental Biology, Sackler School of Medicine, Tel-Aviv University, Tel Aviv 69978, Israel, and Department of Biochemistry, Rush University Medical Center, Chicago, Illinois 60612

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.

Received for publication, March 18, 2008 , and in revised form, June 19, 2008.

^* This work was supported by Arthritis and Research Campaign Grants 16539 and 17950 (to A. J. D. and C. M. M. and to A. S., A. J. D., and C. M. M., respectively) and ISIS Innovation, Oxford Grant POC 228 (to A. S. and A. J. D.). This work was also supported by National Institutes of Health NIAMS Grant AR051163 (to K. M.). Funding was also received from the CellProm Project, FP6th of the European Community (NMP4-CT-2004-500039 (to D. B.)). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

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¹ To whom correspondence may be addressed: Faculty of Life Sciences, University of Manchester, Michael Smith Bldg., Oxford Rd., Manchester, M13 9PT, UK. Tel.: 44-161-2751495; Fax: 44-161-2751505; E-mail: anthony.day{at}manchester.ac.uk. ² To whom correspondence may be addressed. Tel.: 44-1865-227855; Fax: 44-1865-227966; E-mail: afsie.sabokbar{at}ndos.ox.ac.uk. ³ To whom correspondence may be addressed: Faculty of Life Sciences, University of Manchester, Michael Smith Bldg., Oxford Road, Manchester, M13 9PT, UK. Tel.: 44-161-2755061; Fax: 44-161-2751505; E-mail: caroline.milner{at}manchester.ac.uk.

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