INHIBITION OF BOVINE NASAL CARTILAGE DEGRADATION BY SELECTIVE MATRIX METALLOPROTEINASE INHIBITORS

N-terminal analysis of aggrecan fragments lost from bovine nasal carti lage cultured in the presence of recombinant human interleukin la reve aled a predominant ARGSVIL sequence with an additional ADLEX sequence. Production of the ARGSVIL-containing fragments has been attributed to the action of a putative proteinase, aggrecanase. The minor sequence (ADLEX) corresponds to a new reported cleavage product; comparison of this sequence with the available partial sequence of bovine aggrecan i ndicates that this is the product of a cleavage occurring towards the C-terminus of the protein. Matrix metalloproteinase (MMP) inhibitors i nhibited aggrecan loss from bovine nasal explants incubated in the pre sence of recombinant human interleukin la. A strong correlation betwee n inhibition of aggrecan metabolism and inhibition of stromelysin 1 (M MP 3) (r = 0.93) suggests a role for stromelysin or a stromelysin-like enzyme in cartilage aggrecan metabolism. However, the compounds were approx. 1/1000 as potent in inhibiting aggrecan loss from the cartilag e explants as they were in inhibiting stromelysin. There was little or no correlation between inhibition of aggrecan metabolism and inhibiti on of gelatinase B (MMP 9) or inhibition of collagenase 1 (MMP 1). Stu dies with collagenase inhibitors with a range of potencies showed a co rrelation between inhibition of collagenase activity and inhibition of collagen degradation in the cartilage explant assay. This indicates t hat in interleukin 1 alpha-driven bovine nasal cartilage destruction, stromelysin (or a closely related enzyme) is involved in aggrecan meta bolism, whereas collagenase is principally responsible for collagen de gradation.