The aim of this study was to determine if curcumin and quercetin inhibit induced aggrecan loss from bovine articular cartilage explants given that these polyphenols have been shown to suppress the expression of matrix-degrading enzymes. The kinetics of loss of ³⁵S-aggrecan and the loss of total aggrecan in cartilage explants maintained in catabolic medium containing either 1 μM retinoic acid or 50 ng/ml interleukin (IL)-1α were studied in the presence of either 1-25 μM curcumin or 10-50 μM quercetin. The reversibility of catabolism of ³⁵S-aggrecan was also studied in catabolically stimulated cultures treated with 25 μM curcumin or 50 μM quercetin for the initial 4-5 days of culture followed by 10-15 days of culture in catabolic medium in the absence of either polyphenol. Curcumin and quercetin suppressed ³⁵S-aggrecan and total aggrecan loss from the explants in a dose-dependent manner. When the exposure of explants to curcumin or quercetin was limited to the first 4-5 days of culture, the suppression of ³⁵S-aggrecan loss was maintained in the extended culture period when the tissue was stimulated with either retinoic acid or IL-1α. Quercetin suppressed IL-1α-stimulated expression of a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)-4. Curcumin suppressed retinoic acid stimulated expression of ADAMTS-5, and both polyphenols suppressed basal expression of ADAMTS-5. The ability of curcumin and quercetin to protect cartilage from stimulated aggrecan loss and to maintain this protection posttreatment may, at least in part, be due to the suppression of gene expression of ADAMTS-4 and -5.