In their recent article (1), Haas et al described an interesting approach for identification of genes whose expression may be altered in rheumatoid arthritis (RA). They compared messenger RNA (mRNA) expression profiles of lymphoblastoid B cell lines from disease-discordant twins, and further analyzed the 3 genes with strongest overexpression in the cell lines derived from the twins affected with RA. The second most overexpressed gene in RA was that encoding 11β-hydroxysteroid dehydrogenase 2 (11β-HSD2). Protein expression in synovial tissue of patients with RA and osteoarthritis (OA) assessed by immunohistochemistry correlated with the inflammation score, suggesting a link between expression of 11β-HSD2 and the degree of inflammation.
However, the authors repeatedly claim that 11β-HSD2 was never before identified as a gene/enzyme in the context of the alterations in synovial tissue associated with RA. These statements are inaccurate since a study published in this journal (2) demonstrated expression of both 11β-HSD1 and 11β-HSD2 in CD163+ macrophages and CD163− cells (but not in CD3+ lymphocytes or prolyl 4-hydroxylase–positive fibroblasts), by double immunofluorescence labeling of synovial tissue from patients with RA and OA. The ratio of cells positive for 11β-HSD2 versus cells positive for 11β-HSD1 was higher in RA samples (n = 11) than in OA samples (n = 14). 11β-HSD1 predominantly catalyzes the conversion of cortisone into cortisol (i.e., activation), whereas 11β-HSD2 catalyzes the inactivation of cortisol. Thus, the shift of the ratio toward 11β-HSD2 should reduce the availability of anti-inflammatory cortisol within the synovial tissue. Indeed, biochemical analysis has shown that in RA the reactivation of cortisone is impaired, suggesting that the alterations in protein expression are functionally relevant (2).
In a recent study (3), Hardy et al showed that inhibition of interleukin-6 (IL-6) production by cortisone in synovial fibroblasts depends on the activity of 11β-HSD1, i.e., glucocorticoid activation. In another recent study (4), Antoniv and Ivashkiv observed induction of 11β-HSD1 mRNA expression by antiinflammatory IL-10 in synovial macrophages from control subjects, but not by macrophages from RA patients. Thus, the combined results of these studies (1–4) strongly support the hypothesis that a shift toward local inactivation of glucocorticoids within the synovial tissue, most likely caused by alteration of the ratio of expression of 11β-HSD1 and 11β-HSD2, may be a common feature of synovial inflammation in RA.