Antiinflammatory effects of tumor necrosis factor on hematopoietic cells in a murine model of erosive arthritis

Arthritis Rheum. 2010 Jun;62(6):1608-19. doi: 10.1002/art.27399.


Objective: To investigate the mechanisms leading to the influx of inflammatory hematopoietic cells into the synovial membrane and the role of tumor necrosis factor receptor I (TNFRI) and TNFRII in this process in an animal model of rheumatoid arthritis (RA).

Methods: We performed bone marrow transplantations in human TNF-transgenic mice using hematopoietic cells from wild-type, TNFRI(-/-), TNFRII(-/-), and TNFRI/II(-/-) mice as donors and assessed the severity of arthritis histologically. Generation of osteoclasts from the different genotypes was analyzed in vitro and in vivo. Apoptosis was analyzed using annexin V staining as well as TUNEL assays.

Results: Despite lacking responsiveness to TNF in their hematopoietic compartment, mice not only developed full-blown erosive arthritis but even showed increased joint destruction when compared with mice with a TNF-responsive hematopoietic compartment. We demonstrated different roles of the 2 different TNFRs in the regulation of these processes. The absence of TNFRI on hematopoietic cells did not affect joint inflammation but markedly attenuated erosive bone destruction via reduced synovial accumulation of osteoclast precursors. In contrast, the absence of TNFRII on hematopoietic cells increased joint inflammation as well as erosive bone destruction via the regulation of osteoclast precursor apoptosis.

Conclusion: Our findings indicate that selective blockade of TNFRI, leaving the antiinflammatory effects of TNFRII unaltered instead of unselectively blocking TNF, might be advantageous in patients with RA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects*
  • Apoptosis / immunology
  • Arthritis, Rheumatoid / drug therapy*
  • Arthritis, Rheumatoid / immunology
  • Arthritis, Rheumatoid / metabolism
  • Blotting, Western
  • Bone Marrow Transplantation
  • Cell Count
  • Flow Cytometry
  • Humans
  • Immunohistochemistry
  • In Situ Hybridization
  • Mice
  • Mice, Transgenic
  • Osteoclasts / drug effects*
  • Osteoclasts / immunology
  • Osteoclasts / metabolism
  • Receptors, Tumor Necrosis Factor, Type I / immunology
  • Receptors, Tumor Necrosis Factor, Type I / metabolism*
  • Receptors, Tumor Necrosis Factor, Type II / immunology
  • Receptors, Tumor Necrosis Factor, Type II / metabolism*
  • Severity of Illness Index
  • Synovial Membrane / immunology
  • Synovial Membrane / metabolism
  • Tumor Necrosis Factor-alpha / immunology
  • Tumor Necrosis Factor-alpha / metabolism
  • Tumor Necrosis Factor-alpha / pharmacology*


  • Receptors, Tumor Necrosis Factor, Type I
  • Receptors, Tumor Necrosis Factor, Type II
  • Tumor Necrosis Factor-alpha