To examine whether proteoglycans (PGs) liberated from cartilage might contribute to articular changes in arthritis, cartilage PGs were injected intraarticularly into rabbit knee joints. Twice-weekly injections of PG (2.5 mg) provoked synovial hypertrophy, synovitis, erosion of the articulating surfaces, and loss of metachromasia of the articular cartilage. These changes were accompanied by a marked elevation in the production of neutral collagenase and gelatinase by both synoviocytes and chondrocytes. The synoviocytes of experimental knee joints also produced factor(s), possibly related to interleukin-1, which provoked the activation of chondrocytes. Our data are consistent with the idea that free PG fragments mediate some of the pathophysiologic changes that occur in arthritic joints. This property may be particularly important in osteoarthritis.