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

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.