Skip to main content


Isolated and combined inhibition of TNF-, IL-1 and RANKL-pathways in TNF-induced arthritis: effects on synovial inflammation, bone erosion and cartilage destruction

Article metrics

  • 1169 Accesses

To investigate the efficacy of isolated and combined blockade of TNF-, IL-1- and RANKL-pathways on synovial inflammation, bone erosion and cartilage destruction in a TNF-driven arthritis model, human TNF transgenic (hTNFtg) mice were treated with anti-TNF (infliximab), IL-1 receptor antagonist (IL-1Ra) or osteoprotegerin (OPG). In addition, each of three possible double combination therapies and a triple combination therapy was applied. Therapy was followed by histological assessment of synovial inflammation, bone erosion and cartilage damage.

Synovial inflammation was inhibited by anti-TNF (-51%), but not IL-1Ra or OPG monotherapy. Combinations of anti-TNF with IL-1Ra (-91%) or OPG (-81%) were additive and almost completely blocked inflammation. Bone erosion was effectively blocked by anti-TNF (-79%) and also by OPG (-60%), but not by IL-1Ra monotherapy. Combination of anti-TNF and IL-1Ra, however, completely blocked bone erosion (-98%). The effects on inhibition of bone erosion were accompanied by reduction of osteoclast numbers within synovial tissue. Cartilage destruction was inhibited by anti-TNF (-43%), weakly, but not significantly by IL-1Ra, and not at all by OPG monotherapy. Combination of anti-TNF with IL-1Ra was the most effective double combination therapy in preventing cartilage destruction (-80%). In all analyses, a triple combination of anti-TNF, IL-1Ra and OPG was not superior to double combination therapy with anti-TNF and IL-1Ra. Articular changes caused by chronic TNF overexpression are not completely blockable by monotherapies, which target TNF, IL-1 or RANKL. However, combined approaches that reduce TNF load and block IL-1 or RANKL as downstream mediators of TNF can lead to a complete remission. Differences in their efficacy to block synovial inflammation, bone erosion and cartilage destruction further strengthen the rationale for combined blockade of more than one proinflammatory pathway.

Author information

Rights and permissions

Reprints and Permissions

About this article


  • Infliximab
  • Synovial Tissue
  • Bone Erosion
  • Cartilage Damage
  • Cartilage Destruction