Rheumatology Advance Access originally published online on September 16, 2003
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Rheumatology 2004; 43: 164-169
© British Society for Rheumatology 2003; all rights reserved
Basic Science |
Glucocorticoids inhibit induced and non-induced mRNA accumulation of genes encoding hyaluronan synthases (HAS): hydrocortisone inhibits HAS1 activation by blocking the p38 mitogen-activated protein kinase signalling pathway
Ludwig Boltzmann Institute for Rheumatology and Balneology, Kurbadstrasse 10, 1100 Vienna, Austria.
Correspondence to: K. M. Stuhlmeier, Ludwig Boltzmann Institute for Rheumatology and Balneology, Kurbadstrasse 10, POB 78, A-1107 Vienna-Oberlaa, Austria. E-mail: karlms{at}excite.com
Objective. Glucocorticoids are still a mainstay in the treatment of rheumatoid arthritis (RA). Unfettered hyaluronan release is a hallmark of RA. The discovery of three genes encoding hyaluronan synthase (HAS) led us to investigate the effect of hydrocortisone and dexamethasone on the activation of these genes at the molecular level and, at least in part, the mode of action of these drugs.
Methods. Reverse transcription–polymerase chain reaction (RT-PCR) was used to monitor levels of HAS1, HAS2, and HAS3 mRNAs in cultured fibroblast-like synoviocytes (FS) and in leucocytes isolated from synovial fluid of RA patients. Western blot experiments were used to investigate the effect of hydrocortisone on transforming growth factor ß (TGF-ß)-induced activation of the p38 mitogen-activated protein kinase (MAPK) pathway.
Results. Hydrocortisone and dexamethasone suppressed HAS2 and HAS3 mRNAs accumulation concentration-dependently. Contrary to HAS2 and HAS3, HAS1 in FS was not constitutively activated. When cells were stimulated with TGF-ß, a potent activator of HAS1 mRNA transcription, treating them with hydrocortisone suppressed induced activation of HAS1 in a concentration- and time-dependent manner. Similar suppressive effects of hydrocortisone were observed when leucocytes isolated from synovial fluid of inflamed joints were used instead of cultured FS. Furthermore, western blot experiments confirmed that hydrocortisone blocked TGF-ß-induced phosphorylation of p38 MAPK, a kinase essential for TGF-ß-induced HAS activation.
Conclusion. Our data demonstrate that glucocorticoids suppress all genes encoding hyaluronan. We speculate that inhibition of HAS genes might account for the beneficial effect of glucocorticoid treatment, and also for the detrimental effects of long-term use.
KEY WORDS: Hyaluronan, Hyaluron synthase, Glucocorticoid, TGF, p38 MAPK
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