title: TSG-6 regulates bone remodeling through inhibition of osteoblastogenesis and osteoclast activation.
abstract: 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.
authors.affiliation: Nuffield Department of Orthopaedic Surgery, Botnar Research Centre, University of Oxford, Windmill Rd., Headington, Oxford OX3 7LD, United Kingdom.
authors.forename: David J
authors.initials: DJ
authors.lastname: Mahoney
authors.forename: Katalin
authors.initials: K
authors.lastname: Mikecz
authors.forename: Tariq
authors.initials: T
authors.lastname: Ali
authors.forename: Guillaume
authors.initials: G
authors.lastname: Mabilleau
authors.forename: Dafna
authors.initials: D
authors.lastname: Benayahu
authors.forename: Anna
authors.initials: A
authors.lastname: Plaas
authors.forename: Caroline M
authors.initials: CM
authors.lastname: Milner
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Day
authors.forename: Afsaneh
authors.initials: A
authors.lastname: Sabokbar
mesh_terms: D000818:Animals; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D016723:Bone Remodeling / Q000502:physiology*; D001862:Bone Resorption; D015815:Cell Adhesion Molecules / Q000378:metabolism* / Q000502:physiology*; D006801:Humans; D007700:Kinetics; D051379:Mice; D008822:Mice, Transgenic; D041681:NIH 3T3 Cells; D010006:Osteoblasts / Q000166:cytology* / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology* / Q000378:metabolism; D053245:RANK Ligand / Q000378:metabolism*; D011994:Recombinant Proteins / Q000737:chemistry; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: C525718:BMP2 protein, human; C525719:Bmp2 protein, mouse; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins; D015815:Cell Adhesion Molecules; D053245:RANK Ligand; D011994:Recombinant Proteins; C072273:TNFAIP6 protein, human; C513057:Tnfaip6 protein, mouse; D016212:Transforming Growth Factor beta