title: TSG-6 inhibits osteoclast activity via an autocrine mechanism and is functionally synergistic with osteoprotegerin.
abstract: OBJECTIVE
  TSG-6 (the product of tumor necrosis factor [TNF]-stimulated gene 6) has a potent inhibitory effect on RANKL-mediated bone erosion. The aim of this study was to compare the activity of TSG-6 with that of osteoprotegerin (OPG) and to investigate its role as an autocrine modulator of cytokine-mediated osteoclast formation/activation. We also determined TSG-6 expression in inflammatory joint disease.
  
  
  METHODS
  The effects of TSG-6, OPG, and the inflammation mediators TNFα, interleukin-1 (IL-1), and IL-6 on the formation of osteoclasts from peripheral blood mononuclear cells and synovial fluid (SF) macrophages were determined by tartrate-resistant acid phosphatase staining. Lacunar resorption and filamentous actin ring formation were measured as indicators of osteoclast activity. The amount of TSG-6 in culture media or SF was quantified by enzyme-linked immunosorbent assay, and expression of TSG-6 in synovial tissue was assessed by immunohistochemistry.
  
  
  RESULTS
  TSG-6 acted in synergy with OPG to inhibit RANKL-mediated bone resorption and was produced by osteoclast precursors and mature osteoclasts in response to TNFα, IL-1, and IL-6. Expression of TSG-6 correlated with inhibition of lacunar resorption; this effect was ameliorated by an anti-TSG-6 antibody. The level of TSG-6 protein was determined in SF from patients with various arthritides; it was highest in patients with inflammatory conditions such as rheumatoid arthritis, in which it correlated with the amount of TSG-6 immunostaining in the synovium. TSG-6 inhibited the activation but not the formation of osteoclasts from SF macrophages.
  
  
  CONCLUSIONS
  In the presence of inflammatory cytokines, osteoclasts produced TSG-6 at concentrations that are sufficient to inhibit lacunar resorption. This may represent an autocrine mechanism to limit the degree of bone erosion during joint inflammation.
authors.affiliation: University of Oxford, Oxford, UK.
authors.forename: David J
authors.initials: DJ
authors.lastname: Mahoney
authors.forename: Catherine
authors.initials: C
authors.lastname: Swales
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Athanasou
authors.forename: Michele
authors.initials: M
authors.lastname: Bombardieri
authors.forename: Costantino
authors.initials: C
authors.lastname: Pitzalis
authors.forename: Karolina
authors.initials: K
authors.lastname: Kliskey
authors.forename: Mohammed
authors.initials: M
authors.lastname: Sharif
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Day
authors.forename: Caroline M
authors.initials: CM
authors.lastname: Milner
authors.forename: Afsie
authors.initials: A
authors.lastname: Sabokbar
mesh_terms: D000368:Aged; D015535:Arthritis, Psoriatic / Q000473:pathology / Q000503:physiopathology; D001172:Arthritis, Rheumatoid / Q000473:pathology / Q000503:physiopathology; D019898:Autocrine Communication / Q000502:physiology*; D001862:Bone Resorption / Q000473:pathology / Q000503:physiopathology*; D015815:Cell Adhesion Molecules / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000473:pathology; D008297:Male; D020370:Osteoarthritis, Knee / Q000473:pathology / Q000503:physiopathology; D010010:Osteoclasts / Q000187:drug effects* / Q000473:pathology; D053244:Osteoprotegerin / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D015815:Cell Adhesion Molecules; D007375:Interleukin-1; D015850:Interleukin-6; D053244:Osteoprotegerin; C072273:TNFAIP6 protein, human; D014409:Tumor Necrosis Factor-alpha