INHIBITION OF INTERLEUKIN 1-BETA INDUCED RAT AND HUMAN CARTILAGE DEGRADATION INVITRO BY THE METALLOPROTEINASE INHIBITOR U27391

Interleukin 1 induced proteoglycan loss from cartilage in vitro was prevented by a biochemical inhibitor of metalloproteinase activity. The inhibitor also partially relieved the inhibition of proteoglycan synthesis caused by interleukin 1. The loss of glycosaminoglycan by rat and human femoral head cartilage in response to human recombinant interleukin 1beta (rhIL-1beta) was established, and the modulation of this loss by the metalloproteinase inhibitor U27391 was investigated. Rat femoral head cartilage consistently lost glycosaminoglycan in response to rhIL-1beta whereas only a proportion (30%) of normal human femoral head cartilage did so. Concentrations of 10-100 mumol/l U27391 inhibited the action of rhIL-1beta on rat femoral head cartilage, reversing both the loss of glycosaminoglycan and the inhibition of glycosaminoglycan synthesis. U27391 also prevented the reduction in glycosaminoglycan content of those human femoral head cartilage explants responsive to rhIL-1beta. Metalloproteinase inhibition therefore prevents rhIL-1beta induced glycosaminoglycan loss by rat and human femoral head cartilage, suggesting that inhibitors of such enzymes may prove to be of therapeutic benefit in erosive diseases in humans.