Publisher Summary A number of in vitro studies have been performed to determine the mode of action of chondroitin sulfate (CS). It has been demonstrated that CS possesses both anabolic effects on cartilage metabolism and anticatabolic properties. In various models of cartilage culture or of isolated chondrocytes, CS has demonstrated the capacity to stimulate the synthesis of proteoglycans (PGs), aggrecanases, and hyaluronic acid at a high‐molecular weight. In the cultures of human osteoarthritic chondrocytes, CS inhibits collagenolytic activity and the synthesis of stromelysin (matrix metalloproteinases‐3) and it counteracts the negative effects of IL‐1β on PG, collagen type 2, and PGE2 synthesis. CS is also able to prevent the apoptosis of chondrocytes induced in vitro by nitric oxide. Additional in vitro experiments have demonstrated that CS interacts with the elastase of human leukocytes and that it determines a partial inhibition of activity. The effects of CS on various mediators of inflammation and the degradation of cartilage can probably be explained based on its capacity to reduce the nuclear translocation of the transcription factor, NF‐ κB, induced by IL‐1β.