Article Text

PDF
THU0069 Effects of Anti-TNF-Alpha Therapy on the Recruitment and Availability of Osteoclast Precursors in a Model of Rheumatoid Arthritis
  1. S.S. Uster1,
  2. F.M. Coelho2,
  3. R.M. Ransohoff3,
  4. I.F. Charo4,
  5. B. Engelhardt5,
  6. J.V. Stein5,
  7. W. Hofstetter6,
  8. D. Aeberli1,
  9. M. Seitz1
  1. 1Department of Rheumatology, Immunology and Allergology, University Hospital Bern
  2. 2Institute for Infectious Diseases, Bern, Switzerland
  3. 3Department of Neurosciences, Lerner Research Institute, Cleveland
  4. 4Gladstone Institute of Cardiovascular Research, San Francisco, United States
  5. 5Theodor Kocher Institute
  6. 6Department of Clinical Research, Bern, Switzerland

Abstract

Background Rheumatoid Arthritis (RA) is an inflammatory autoimmune disease which is associated with local and systemic loss of bone that is mediated by the increased activity and number of bone resorbing osteoclasts (1). The improvement of bone lesions in RA patients under anti-tumor necrosis factor (TNF)-α therapy links this cytokine firmly to the process of bone loss (2). Besides the critical role of TNF-α in the localized inflammatory process within the joint, it has been suggested that TNF-α may additionally modulate the recruitment of osteoclast precursors from the bone marrow to the site of inflammation (3). However, to which degree TNF-α has an effect on osteoclast precursor trafficking is still largely unknown.

Objectives The goal of this study is to investigate the effects of TNF-α on the recruitment steps of osteoclast precursors from the bone marrow to the arthritic joint.

Methods Monocyte subsets from heterozygous CX3CR1-GFP knock-in mice were sorted by flow cytometry and their potential to differentiate into osteoclasts was analyzed in vitro. The antigen-induced arthritis model was used to further analyze these osteoclast precursor populations in vivo. Arthritic animals were treated with a soluble TNF receptor (etanercept) and histology of the joint revealed the therapeutic effect of the anti-TNF-α therapy. The bone marrow, blood and knee cellularity were analyzed by flow cytometry.

Results The potential of monocytes to differentiate into osteoclasts in vitro was strictly restricted to the classical monocyte subset. Already after few days of anti-TNF therapy, the treated animals showed a conversion of the monocyte subset ratio in the blood: Significantly more non-classical monocytes were found in the circulation. This ratio stayed unchanged over the time of treatment. Whereas the joint was still highly inflamed in the acute phase, two weeks of anti-TNF therapy resulted in an improved histopathology of the arthritic joint. Interestingly, the bone marrow cellularity did not seem to be altered by the TNF-α blockade in early and late stages of the disease.

Conclusions Our observations indicate that TNF-α depletion induces a rapid change in the availability of osteoclast precursors in the circulation over the time during the treatment, resulting after two weeks of anti-TNF treatment in significantly lower numbers of bone lesions and leukocyte infiltration at the joint site. The osteoclast precursor cell population in the bone marrow was not affected over time by the anti-TNF-α treatment.

References

  1. McInnes and Schett (2011). The pathogenesis of rheumatoid arthritis.

  2. Kitaura, et al. (2013). Immunological reaction in TNF-α-mediated osteoclast formation and bone resorption in vitro and in vivo.

  3. Zhang, et al. (2008). TNF inhibits production of stromal cell-derived factor 1 by bone stromal cells and increases osteoclast precursor mobilization from bone marrow to peripheral blood.

Disclosure of Interest None declared

Statistics from Altmetric.com

Request permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.