Effect of diacetyl rhein on the development of experimental osteoarthritis. A biochemical investigation.
OBJECTIVE
To investigate the effect of diacetyl rhein (DAR) on the synthesis, turnover and composition of cartilage in an experimental model of osteoarthritis in beagle bitches.


METHODS
Osteoarthritis was induced in mature beagle bitches by the transection of the cranial cruciate ligament. Six animals received DAR 20 mg/kg daily for 11 weeks. A matched group received empty capsules daily for the same period. At 11 weeks, articular cartilage was examined for the ratio of the 6:4-sulfated disaccharides of chondroitin and the tissue concentration of hydroxyproline and glycosaminoglycan. In addition, labeling studies were performed to estimate the effect of DAR on proteoglycan synthesis and turnover.


RESULTS
DAR had no effect on body weight or food consumption but induced a mild diarrhea and slightly increased the incidence of vomiting. DAR tended to reduce proteoglycan synthesis, however, DAR did reduce proteoglycan turnover in the femoral cartilage. DAR produced changes in the composition of the osteoarthritic cartilage that could only partly be accounted for by changes in hydration and/or swelling. In addition, it was noted that induction of osteoarthritis increased the ratio of chondroitin 6-sulfated to chondroitin 4-sulfated disaccharides; DAR reduced the ratio in tibial plateau cartilage from osteoarthritic joints compared with untreated tissue from osteoarthritic joints. DAR showed moderate reduction on the biosynthesis of proteoglycans. DAR also produced a reduction in proteoglycan turnover from all anatomical areas compared with non-treated controls in both the lateral and medial femoral condyles.


CONCLUSIONS
DAR was well tolerated by the experimental animals, but did not produce significant changes in the synthesis or turnover of proteoglycans. The slight reduction in proteoglycan synthesis may prove to be biologically significant after chronic dosing. DAR's effects on the hydroxyproline and glycosaminoglycan content suggest, however, that it must influence the swelling of cartilage and loss of glycosaminoglycan. This indicates that small changes can translate, to significant differences in cartilage composition over an 11-week time period.
Carney
S L
SL
Osteoarthritis Department, Lilly Research Centre Ltd., Windlesham, Surrey, UK.
D000818:Animals; D000880:Anthraquinones / Q000627:therapeutic use*; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D015415:Biomarkers; D002358:Cartilage, Articular / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D002809:Chondroitin Sulfates / Q000378:metabolism; D004195:Disease Models, Animal; D004285:Dogs; D000939:Epitopes / Q000378:metabolism; D006025:Glycosaminoglycans / Q000378:metabolism; D006909:Hydroxyproline / Q000378:metabolism; D010003:Osteoarthritis / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D011509:Proteoglycans / Q000096:biosynthesis* / Q000187:drug effects
D000880:Anthraquinones; D000894:Anti-Inflammatory Agents, Non-Steroidal; D015415:Biomarkers; D000939:Epitopes; D006025:Glycosaminoglycans; D011509:Proteoglycans; C025292:diacerein; D002809:Chondroitin Sulfates; D006909:Hydroxyproline