The transcription factors hypoxia-inducible factor 1alpha and Ets-1 colocalize in the hypoxic synovium of inflamed joints in adjuvant-induced arthritis

Arthritis Rheum. 2004 Jan;50(1):291-6. doi: 10.1002/art.11473.


Objective: To determine the relationship between hypoxia and the expression of Ets-1 and hypoxia-inducible factor 1alpha (HIF-1alpha) in both normal and inflamed joints. Adjuvant-induced arthritis (AIA) was used as the model system, since it mirrors many aspects of the pathology of rheumatoid arthritis.

Methods: Adjuvant arthritis was induced in a group of 10 female Lewis rats. A second group of 10 uninjected female Lewis rats served as naive controls. When a maximum clinical joint score was achieved in the AIA group, all 20 rats were injected with the specific hypoxic cell marker Hypoxyprobe-1 and subsequently killed. Hypoxyprobe-1 adducts, Ets-1, and HIF-1alpha were localized in the joints of the hind feet from these groups using immunohistochemistry.

Results: Compared with the joints from control rats, inflamed joints contained markedly more cells with Hypoxyprobe-1 adduct immunoreactivity, Ets-1-immunoreactive nuclei, and nuclear immunoreactivity for both Ets-1 and HIF-1alpha.

Conclusion: Our results demonstrate the presence of hypoxia in inflamed joints in this experimental model of arthritis. The colocalization of Ets-1 and HIF-1alpha in these hypoxic areas suggests that hypoxia may induce Ets-1 and HIF-1alpha expression during joint inflammation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arthritis, Experimental / metabolism*
  • Arthritis, Experimental / pathology
  • Disease Models, Animal
  • Female
  • Hypoxia / metabolism*
  • Hypoxia / pathology
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Immunohistochemistry
  • Proto-Oncogene Protein c-ets-1
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-ets
  • Rats
  • Rats, Inbred Lew
  • Synovial Membrane / metabolism
  • Synovial Membrane / pathology
  • Synovitis / metabolism*
  • Synovitis / pathology
  • Transcription Factors / metabolism*


  • Ets1 protein, rat
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Proto-Oncogene Protein c-ets-1
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-ets
  • Transcription Factors