Stimulating effect of diacerein on TGF-beta 1 and beta 2 expression in articular chondrocytes cultured with and without interleukin-1

Objective: Diacetylrhein or diacerein has shown efficacy in the treatment o f both major forms of osteoarthritis (OA), coxarthrosis as well as gonarthr osis, improving clinical symptoms of the disease (pain reduction and algo-f unctional index). Both in-vitro and animal models studies suggest that diac erein may have also disease-modifying effects. The drug exerts inhibitory e ffects on interleukin-l-induced expression of cartilage degrading enzymes. However, its mechanism of action is not completely understood. In view of t he role that could play the transforming growth factor (TGF)-beta system in the repair potentialities of OA cartilage, we studied the effect of diacer ein on the expression of TGF-beta isoforms 1, 2 and 3 and that of their rec eptor types I and II in cultured bovine chondrocytes. Methods: Cultured bovine articular chondrocytes were treated with 10(-5) M diacerein, 10ng/ml IL-1 beta or the combination diacerein + interleukin (IL )-1, and the expression of both TGF-beta isoforms 1, 2 and 3 and that of th eir receptors T beta R-I and T beta R-II was determined by Northern-blot an d reverse transcriptase-polymerase chain reaction (RT-PCR). Cell transfecti ons of cDNA constructs containing sequences of the 5'-upstream region of TG F-beta 1 promoter were also performed to determine their transcriptional ac tivity in diacerein-treated cultures. Results: The data indicated that diacerein enhances the expression of TGF-b eta 1 and TGF-beta 2. This effect was also found in the presence of IL-1, a lbeit with smaller intensity. In contrast, the levels of TGF-beta 3 and rec eptors I and II remained unaffected or slighty modified by the compound. Tr eatment of cells transiently transfected with TGF-beta 1 promoter construct s suggested that the stimulating effect on TGF-beta 1 expression is mediate d by the region -1038 to -1132 base pars. Conclusion: The results suggest that diacerein effects on matrix synthesis and turn-over previously reported in cultured articular chondrocytes might be explained in part by the ability of the drug to enhance TGF-beta 1 and T GF-beta 3 expression in these cells. This mechanism of action may account f or the potential disease-modifying properties of diacerein and might give c lues as to how future anti-osteoarthritic drugs should be designed.