INHIBITION OF CARTILAGE PROTEOGLYCAN RELEASE BY A SPECIFIC INACTIVATOR OF CATHEPSIN-B AND AN INHIBITOR OF MATRIX METALLOPROTEINASES - EVIDENCE FOR 2 CONVERGING PATHWAYS OF CHONDROCYTE-MEDIATED PROTEOGLYCAN DEGRADATION

Objective. To investigate mechanisms of cartilage matrix destruction b y a study of the effects of a specific inactivator of cathepsin B and an inhibitor of several matrix metalloproteinases (MMP) on cartilage p roteoglycan release. Methods. Cartilage explants were treated with eit her recombinant human interleukin-1alpha (rHuIL-1alpha) or retinoic ac id in the presence or absence of the inhibitors, and proteoglycan rele ase was quantitated. Tests for nonspecific effects of the inhibitors i ncluded reversibility, rates of protein synthesis and glycolysis, and effects on other rHuIL-1alpha-mediated events. Results. The cathepsin B inactivator inhibited rHuIL-1alpha-stimulated proteoglycan release a t nanomolar concentrations, but failed to significantly inhibit retino ic acid-stimulated proteoglycan release. An inhibitor of MMP was inhib itory to both rHuIL-1alpha-stimulated release and retinoic acid-stimul ated release. Conclusion. Cathepsin B is implicated in rHuIL-1alpha-st imulated loss of cartilage proteoglycan. Its lack of involvement in re tinoic acid-stimulated proteoglycan release suggests the existence of at least 2 pathways of cartilage proteoglycan breakdown, which may con verge at the activation of a matrix prometalloproteinase.