Cytokine-controlled RANKL and osteoprotegerin expression by human and mouse synovial fibroblasts: fibroblast-mediated pathologic bone resorption

Arthritis Rheum. 2008 Aug;58(8):2397-408. doi: 10.1002/art.23653.

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.

Conclusion: 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arthritis, Rheumatoid / metabolism
  • Arthritis, Rheumatoid / pathology
  • Bone Resorption / metabolism*
  • Bone Resorption / pathology
  • Cells, Cultured
  • Cytokines / pharmacology*
  • Dose-Response Relationship, Drug
  • Fibroblasts / cytology
  • Fibroblasts / metabolism*
  • Fibroblasts / pathology
  • Humans
  • Interferon-gamma / genetics
  • Interferon-gamma / metabolism
  • Interleukin-17 / pharmacology
  • Interleukin-1beta / pharmacology
  • Interleukin-4 / genetics
  • Interleukin-4 / metabolism
  • Mice
  • Mice, Inbred BALB C
  • Mice, Knockout
  • Osteoprotegerin / metabolism*
  • RANK Ligand / metabolism*
  • Synovial Membrane / cytology
  • Synovial Membrane / metabolism*
  • Synovial Membrane / pathology
  • Tumor Necrosis Factor-alpha / pharmacology

Substances

  • Cytokines
  • Interleukin-17
  • Interleukin-1beta
  • Osteoprotegerin
  • RANK Ligand
  • TNFSF11 protein, human
  • Tnfsf11 protein, mouse
  • Tumor Necrosis Factor-alpha
  • Interleukin-4
  • Interferon-gamma