EFFECTS OF DIACERHEIN ON GRANULOMA INDUCED CARTILAGE BREAKDOWN IN THEMOUSE

Objective: Diacerhein, an anti-osteoarthritic agent, was tested for it s ability to suppress synthesis of proinflammatory cytokines in a mode l of granuloma-induced cartilage breakdown. Design: 50 TO mice receive d a subcutaneous implant of cotton-wrapped rat femoral head cartilage for a period of 2 weeks. Animals (N=10/group) were dosed daily with ei ther 6 mg/kg p.o. diclofenac or diacetylrhein at 5, 15 or 50 mg/kg p.o . in 0.1 ml 1% gum tragacanth which served as a control. implanted car tilages were assayed for glycosaminoglycan (GAG) and hydroxyproline co ntent. The surrounding granulomas were assayed for interleukin-la (IL- 1 alpha), tumour necrosis factor-alpha (TNF-alpha) and IL-6. Statistic al analysis was by Mann-Whitney U test. Results: Diclofenac had no sig nificant effect on GAG or hydroxyproline content of implanted cartilag e or on granuloma cytokine concentrations. Diacerhein protected implan ted cartilages against hydroxyproline loss, implanted control cartilag es contained 220 mu g hydroxyproline compared with diacerhein at 5, 15 and 50 mg/kg which produced a 21, 16 and 59% decrease in hydroxyproli ne loss compared with non-implanted controls (P < 0.05, 0.05 and 0.001 ) respectively. Diacerhein also protected against GAG loss at 5 mg/kg and 50 mg/kg, control cartilages contained 134 mu g GAG; compared with diacerhein at 5 mg/kg and 50 mg/kg which produced a 24 and 38% decrea se in GAG loss respectively (P < 0.05 for both). Diacerhein significan tly reduced granuloma interleukin-lu content at 5 mg/kg (control level of 2.4 mu g/ml reduced by 58%; P < 0.05), reduced TNF-alpha at 5 mg/k g and 15 mg/kg (reduced by 61%: P < 0.01 and 49%: P < 0.05 respectivel y; control level of 469 pg/ml) and reduced IL-6 at 15 mg/kg and 50 mg/ kg (control level of 537 pg/ml reduced by 60 and 51%, respectively; P < 0.01 for both). Conclusions: The mechanism of the chondroprotective effects of diacerhein is not understood but may be explained by a redu ction in the concentrations of proinflammatory cytokines.