EFFECTS OF THE HYDROXAMIC ACID DERIVATE RO-31-4724 ON THE METABOLISM AND MORPHOLOGY OF INTERLEUKIN-1-TREATED CARTILAGE EXPLANTS

Matrix metalloproteinases (MMPs) belong to the key enzymes of the prot eolytic destruction of cartilage matrix during chronic rheumatic disea ses. Our work focused on the inhibitory potential of the hydroxamate R o 31-4724 on the activity of MMP-proteoglycanases as well as on the vi ability, morphology and proteoglycan metabolism of interleukin-1 (IL-1 )-treated bovine articular cartilage explants. The in vitro activity o f MMP-proteoglycanases as well as the release of proteoglycans from IL -1-treated cartilage explants were significantly and concentration-dep endently inhibited by Ro 31-4724 tested at concentrations ranging from 1 nmol/l to 10 mu mol/l. Histopathological evaluation of sections fro m cartilage explants treated with this drug revealed no microscopicall y discernible alterations, and did not show any cytotoxic effects of R o 31-4724. In addition, Ro 31-4724 had no effect on the rate of proteo glycan biosynthesis by IL-1-treated cartilage explants and increased t he percentage of newly synthesized proteoglycans to form macromolecula r aggregates. In conclusion, Ro 31-4724 displayed MMP-proteoglycanase inhibitory activity both in vitro and ex vivo and proved to be not har mful to the morphology, viability and proteoglycan biosynthesis of bov ine articular cartilage explants.