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Punicalagin (PA) not only binds type II collagen, but also blocks its MMP‐13‐mediated degradation, and genipin (GNP) is a collagen cross‐linking agent. We hypothesized that these drugs could mitigate the loss of cartilage if administered in the early phase of osteoarthritis, and experiments were designed to provide proof‐of‐concept. Porcine cartilage was exposed to both drugs in a manner designed to simulate intra‐articular (IA) injection. Based on penetration of PA into cartilage, the rate of drug diffusion was conservatively estimated at 2 μm per minute. GNP caused a measurable degree of cross‐linking, increased compressive resistance and coefficient of friction, and substantially inhibited degradation by collagenase, but not by hyaluronidase. Pre‐incubation of GNP with collagenase had no effect on enzymatic activity. PA did not cross‐link collagen nor affect the mechanical properties of cartilage. It did, however, increase resistance to degradation by collagenase and hyaluronidase. Furthermore, it reacted with collagenase in solution and inhibited its subsequent enzymatic activity. Effects of PA and GNP were not additive. The chondroprotective effect of semi‐weekly IA injections was investigated in the monoiodoacetate‐induced model of OA in rats. Quantitative histology suggested that injection of PA decreased the amount of cartilage lost compared to saline‐injected controls, and the addition of GNP made no difference. This study supports the notion that IA delivery of PA could mitigate OA‐induced cartilage erosion. [ABSTRACT FROM AUTHOR]