Diacerhein and rhein reduce the ICE-induced IL-1 beta and IL-18 activationin human osteoarthritic cartilage

Objective: IL-1 beta plays a fundamental role in osteoarthritis (OA) pathop hysiology and cartilage destruction. Targeting the activation mechanism of this cytokine appears to be important as a therapeutic approach. As the int erleukin-l converting enzyme (ICE) is the physiologic modulator of the prod uction of active IL-1 beta, we investigated the effect of diacerhein and it s active metabolite rhein used in the treatment of OA patients, on the enzy me expression and synthesis on human OA cartilage. Further, we looked at th e effect of both drugs on the production of the active form of IL-1 beta an d IL-18. Methods: The expression and synthesis of ICE were investigated on human OA cartilage explants using in-situ hybridization and immunohistochemical meth ods, respectively. The effect of the drugs on ICE OA chondrocytes was also determined by Northern blotting and a specific ELISA assay. Furthermore, th e effect of both drugs on the level of active IL-1 beta and IL-18 was exami ned by immunohistochemistry. Results: Data showed that diacerhein and rhein have no true effect on reduc ing total ICE mRNA by both Northern blotting analysis and in-situ hybridiza tion. A marked and statistically significant decrease was, however, found f or protein production. ELISA showed a reduction of 31% (P<0.04) for diacerh ein and 50% (P<0.02) for rhein. The drugs' immunohistological cell score re duction was similar to data from the ELISA, and a statistical significant r eduction of ICE production was found at both superficial and deep zones of the cartilage. IL-1 beta and IL-18 were both preferentially produced in cho ndrocytes of the superficial zone. For each of these cytokines, both drugs demonstrated a statistically significant decrease in this zone. A marked de crease was also noted in the deep zone, but statistical significance was re ached only for rhein. Conclusion: These results provide a novel regulatory mechanism by which dia cerhein and rhein could exert a down-regulation on IL-l's effect on OA cart ilage. (C) 2000 OsteoArthritis Research Society International.