Central role of the MEK/ERK MAP kinase pathway in a mouse model of rheumatoid arthritis: potential proinflammatory mechanisms

Arthritis Rheum. 2007 Oct;56(10):3347-57. doi: 10.1002/art.22869.


Objective: To evaluate the role of the MEK/ERK MAP kinase pathway in murine collagen-induced arthritis (CIA) using the selective MEK inhibitor PD184352. We examined the effects of the inhibitor in cytokine-stimulated synovial fibroblasts and in cytokine-induced arthritis in rabbits to investigate its antiinflammatory mechanisms.

Methods: Murine CIA was used to assess the effects of the selective MEK inhibitor on paw edema, clinical scores, weight loss, histopathologic features, and joint levels of p-ERK. Western blotting and immunohistochemistry techniques were used to assess p-ERK in human and rabbit synovial fibroblasts and synovial tissue from rheumatoid arthritis (RA) patients. Interleukin-1alpha (IL-1alpha)-stimulated stromelysin production in rabbit synovial fibroblasts was assessed by enzyme-linked immunosorbent assay. A rabbit IL-1alpha-induced arthritis model was used to assess the effects of the inhibitor on IL-1alpha-induced MEK activity, stromelysin production, and cartilage degradation.

Results: In the CIA model, PD184352 inhibited paw edema and clinical arthritis scores in a dose-dependent manner. Disease-induced weight loss and histopathologic changes were also significantly improved by treatment. Inhibition of disease-induced p-ERK levels in the joints was seen with the inhibitor. Levels of p-ERK in the synovium were higher in RA patients than in normal individuals. PD184352 reduced IL-1alpha-induced p-ERK levels in human RA synovial fibroblasts. The production of p-ERK and stromelysin was also inhibited in IL-1alpha-stimulated rabbit synovial fibroblasts. We observed IL-1alpha-induced p-ERK in the synovial lining, subsynovial vasculature, and articular chondrocytes. IL-1alpha-induced stromelysin production and proteoglycan loss from the articular cartilage were reduced by PD184352.

Conclusion: These data demonstrate the inhibition of murine CIA by PD184352, support the hypothesis that antiinflammatory activity contributes to the mechanism of action of the inhibitor, and suggest that a selective inhibitor may effectively treat RA and other inflammatory disorders.

MeSH terms

  • Animals
  • Arthritis, Rheumatoid / drug therapy
  • Arthritis, Rheumatoid / enzymology*
  • Benzamides / pharmacology*
  • Blotting, Western
  • Cartilage, Articular / drug effects
  • Cartilage, Articular / enzymology
  • Disease Models, Animal
  • Enzyme Inhibitors / pharmacology*
  • Extracellular Signal-Regulated MAP Kinases / drug effects*
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Female
  • Fibroblasts / drug effects
  • Fibroblasts / enzymology
  • Immunohistochemistry
  • In Vitro Techniques
  • MAP Kinase Kinase Kinases / drug effects*
  • MAP Kinase Kinase Kinases / metabolism
  • Male
  • Mice
  • Mice, Inbred DBA
  • Rabbits


  • 2-(2-chloro-4-iodophenylamino)-N-cyclopropylmethoxy-3,4-difluorobenzamide
  • Benzamides
  • Enzyme Inhibitors
  • Extracellular Signal-Regulated MAP Kinases
  • MAP Kinase Kinase Kinases