Effects of diacerhein on granuloma induced cartilage breakdown in the mouse.
OBJECTIVE
Diacerhein, an anti-osteoarthritic agent, was tested for its ability to suppress synthesis of proinflammatory cytokines in a model of granuloma-induced cartilage breakdown.


METHODS
50 TO mice received a subcutaneous implant of cotton-wrapped rat femoral head cartilage for a period of 2 weeks. Animals (N = 10/group) were dosed daily with either 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 cartilages were assayed for glycosaminoglycan (GAG) and hydroxyproline content. The surrounding granulomas were assayed for interleukin-1 alpha (IL-1 alpha), tumour necrosis factor-alpha (TNF-alpha) and IL-6. Statistical analysis was by Mann-Whitney U test.


RESULTS
Diclofenac had no significant effect on GAG or hydroxyproline content of implanted cartilage or on granuloma cytokine concentrations. Diacerhein protected implanted cartilages against hydroxyproline loss, implanted control cartilages contained 220 micrograms hydroxyproline compared with diacerhein at 5, 15 and 50 mg/kg which produced a 21, 16 and 59% decrease in hydroxyproline 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 micrograms GAG compared with diacerhein at 5 mg/kg and 50 mg/kg which produced a 24 and 38% decrease in GAG loss respectively (P < 0.05 for both). Diacerhein significantly reduced granuloma interleukin-1 alpha content at 5 mg/kg (control level of 2.4 micrograms/ml reduced by 58%; P < 0.05), reduced TNF-alpha at 5 mg/kg and 15 mg/kg (reduced by 61%: P < 0.01 and 49%: P < 0.05 respectively; 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 reduction in the concentrations of proinflammatory cytokines.
Moore
A R
AR
Department of Experimental Pathology, William Harvey Research Institute, London, U.K.
Greenslade
K J
KJ
Alam
C A
CA
Willoughby
D A
DA
D000818:Animals; D000880:Anthraquinones / Q000494:pharmacology*; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D002358:Cartilage, Articular / Q000737:chemistry* / Q000637:transplantation; D016207:Cytokines / Q000032:analysis; D004008:Diclofenac / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D006025:Glycosaminoglycans / Q000032:analysis; D006099:Granuloma / Q000150:complications / Q000378:metabolism*; D006909:Hydroxyproline / Q000032:analysis; D008297:Male; D051379:Mice; D010003:Osteoarthritis / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D051381:Rats; D017208:Rats, Wistar
D000880:Anthraquinones; D000894:Anti-Inflammatory Agents, Non-Steroidal; D016207:Cytokines; D006025:Glycosaminoglycans; D004008:Diclofenac; C025292:diacerein; D006909:Hydroxyproline