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(American Journal of Pathology. 2003;163:901-911.)
© 2003 American Society for Investigative Pathology

Detection of Oncofetal H19 RNA in Rheumatoid Arthritis Synovial Tissue

Bruno Stuhlmüller^*, Elke Kunisch, Juliane Franz^*, Lorena Martinez-Gamboa^*, Maria M. Hernandez^*, Axel Pruss, Norbert Ulbrich, Volker A. Erdmann, Gerd R. Burmester^* and Raimund W. Kinne

From the Department of Rheumatology^* and the Institute for Transfusion Medicine (Tissue Bank), Charité University Hospital, Humboldt University of Berlin, Berlin; the Experimental Rheumatology Unit, Interdisciplinary Center for Clinical Research, Friedrich Schiller University Jena, Jena; and the Department of Biochemistry, Free University of Berlin, Berlin, Germany

The expression of oncofetal H19 RNA and its localization/cellular source was analyzed in synovial tissue (ST) and isolated synovial macrophages (M) or synovial fibroblasts (SFBs) by reverse transcriptase-polymerase chain reaction (RT-PCR), in situ hybridization, and immunohistochemistry. RT-PCR showed significantly higher H19 expression in ST from patients with rheumatoid arthritis (RA) (P = 0.000) and osteoarthritis (OA) (P = 0.009) than in normal/joint trauma controls (N/JT), but comparable levels in reactive arthritis. In situ hybridization demonstrated strong signals in all RA-ST samples (n = 8), with 85% positive cells in the lining layer, diffuse infiltrates, and stroma regions. In lymphoid aggregates and endothelial cells only 20% were positive. RA-ST contained a significantly higher percentage of strongly positive lining cells than OA-ST and N/JT-ST. H19 RNA was expressed in both M and SFBs, as confirmed by RT-PCR in isolated RA M and SFBs (n = 3). In RA-SFBs, low constitutive H19 RNA expression in culture (10% fetal calf serum) was strongly increased on starvation (3.5-fold, 1% fetal calf serum), with or without the addition of interleukin-1ß (10 to 100 U/ml), tumor necrosis factor- (1 to 25 ng/ml), or platelet-derived growth factor-BB (2.5 to 10 U/ml). In OA-SFBs, this starvation-induced increase was lower (twofold), reaching significant differences compared with RA-SFBs after stimulation with interleukin-1ß and platelet-derived growth factor-BB. In both RA- and OA-SFBs, the MAP-kinase ERK-1/2 pathway and the phosphatidylinositol-3 kinase pathway influenced H19 RNA expression, as shown by inhibitor studies. Significant overexpression of H19 RNA and its increased sensitivity to starvation/cytokine regulation in RA suggests a pathogenetic role of this oncofetal gene, possibly reflecting embryonal dedifferentiation of the adult ST and/or ongoing inflammatory/oxidative stress.

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