Background Rheumatoid Arthritis is an autoimmune inflammatory disease. A glucocorticoid resistance has been postulated as a factor involved in the pathogenesis of this disease.1 The mechanisms involved in this GC-resistance has not been elucidated. Glucocorticoids´ effects are mediated trough an intracelular receptor, the glucocorticoid receptor (GCR). Thereare two isoforms of the GCR termed alpha and beta. The Beta isoform has recently been demostrated to act as a dominant negative inhibitor of the classic glucocorticoid receptor alpha.2 As a potential in vivo inhibitor of GCR alpha activity, the expression of GCR beta isoform may be an important factor regulating target cell responsiveness to glucocorticoids.
Objectives This study evaluated if there is an increase in GCR beta mRNA in peripheral blood mononuclear cells (PBMNC) from active newly diagnosed rheumatoid arthritis (RA) patients as compared to PBMNC from normal controls.
Methods PBMNC were obtained from 9 active RA patients and 9 normal controls, matched by age and sex. A patient was defined as having an active disease if 3 of the following criteria were fulfilled: Erytrosedimentation rate > 30 mm/hour, morning stiffness > 1 h, >6 tender joints, > 3 swollen joints. The GCR alpha and beta were evaluated by semiquantitative RT-PCR. The RT-PCR products for both isoforms of glucocorticoid receptor were electrophoretically fractioned on 2% agarose gels stained with ethidium bromide. The intensity of ethdium bromude fluorescence was measured densitometrically and expressed as optical density units (ODU). The presence of statistically significant differences in ODU between groups was evaluated by the Wilcoxon test for matched pairs.
Results RA patients presented a significant increase in the expression of GCR beta mRNA (median 571, range 208–968 ODU vs median 317, range 83–563 ODU in controls; P = 0.007) with no change in GCR alpha mRNA compared to controls.
Conclusion RA patients present an increased expresion of the inhibitory beta isoform of the GCR in PBMNC. Glucocorticoids have well known anti-inflammatory properties, therefore an increased proportion of the inhibitory isoform of the glucocorticoid receptor could lead to a glucocorticoid-resistance status, wich could be a pathogenetic factor in RA by favouring the persistence of inflammatory processes.
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Bamberger CM, Bamberger AM, de Castro M, Chrousos GP. Glucocorticoid receptor beta a potential endogenous inhibitor of glucocorticoid actions in humans. J Clin Invest. 1995;95:2435–41
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