title: Cytokine-controlled RANKL and osteoprotegerin expression by human and mouse synovial fibroblasts: fibroblast-mediated pathologic bone resorption.
abstract: OBJECTIVE
  To determine whether proinflammatory cytokine treatment or the complete absence of select cytokines modulates the expression of RANKL and osteoprotegerin (OPG) in synovial fibroblasts.
  
  
  METHODS
  Fibroblasts were isolated from normal and rheumatoid human synovium and from normal or arthritic joints of wild-type and cytokine gene-deficient (interleukin-4-knockout [IL-4 (-/-)] and interferon-gamma-knockout [IFNgamma (-/-)]) mice. Fibroblasts were stimulated with proinflammatory cytokines (tumor necrosis factor alpha [TNFalpha], IL-1beta, and IL-17) or antiosteoclastogenic cytokines (IL-4 and IFNgamma), alone or in combination, and the expression of RANKL and OPG was measured.
  
  
  RESULTS
  Proinflammatory cytokine-stimulated fibroblasts from rheumatoid and arthritic mouse joints expressed higher levels of RANKL and OPG than those from normal joints. IL-4 suppressed RANKL expression and increased OPG expression, IFNgamma reduced the production of both RANKL and OPG, and IL-17 had only a modest effect on the expression of RANKL or OPG. Additive effects of combination treatment (TNFalpha/IL-17 or IL-1beta/IL-17) were observed only in the human system. Extensive destruction was observed in the arthritic joints of IL-4 (-/-) mice, with a corresponding upward shift of the RANKL:OPG ratios. However, an IL-17 deficiency did not attenuate arthritis or reduce bone resorption.
  
  
  CONCLUSIONS
  Proinflammatory cytokines induce the expression of RANKL and OPG in both human and murine synovial fibroblasts. The RANKL:OPG ratios are shifted in favor of bone protection by IL-4 treatment, and, to a lesser extent, by IFNgamma treatment. Unexpectedly, an IL-17 deficiency alone does not induce reduced inflammatory bone destruction. Our results suggest that synovial fibroblasts may significantly contribute to bone resorption through modulation of RANKL and OPG production in a cytokine-rich milieu of inflamed joints.
authors.affiliation: Department of Orthopedic Surgery, Rush University Medical Center, Cohn Research Building, Chicago, IL 60612, USA.
authors.forename: Miklos
authors.initials: M
authors.lastname: Tunyogi-Csapo
authors.forename: Katalin
authors.initials: K
authors.lastname: Kis-Toth
authors.forename: Marianna
authors.initials: M
authors.lastname: Radacs
authors.forename: Balint
authors.initials: B
authors.lastname: Farkas
authors.forename: Joshua J
authors.initials: JJ
authors.lastname: Jacobs
authors.forename: Alison
authors.initials: A
authors.lastname: Finnegan
authors.forename: Katalin
authors.initials: K
authors.lastname: Mikecz
authors.forename: Tibor T
authors.initials: TT
authors.lastname: Glant
mesh_terms: D000818:Animals; D001172:Arthritis, Rheumatoid / Q000378:metabolism / Q000473:pathology; D001862:Bone Resorption / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism; D020381:Interleukin-17 / Q000494:pharmacology; D053583:Interleukin-1beta / Q000494:pharmacology; D015847:Interleukin-4 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D053244:Osteoprotegerin / Q000378:metabolism*; D053245:RANK Ligand / Q000378:metabolism*; D013583:Synovial Membrane / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D016207:Cytokines; D020381:Interleukin-17; D053583:Interleukin-1beta; D053244:Osteoprotegerin; D053245:RANK Ligand; C505688:TNFSF11 protein, human; C505689:Tnfsf11 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D015847:Interleukin-4; D007371:Interferon-gamma