Pharmacological influence of antirheumatic drugs on proteoglycanases from interleukin-1 treated articular cartilage

Abstract

The purpose of this study was to examine whether drugs used in the treatment of arthritic disorders possess any inhibitory potential on the proteoglycanolytic activities of matrix metalloproteinases (MMPs), and to determine whether drugs which inhibit these enzymes also modulate the biosynthesis and release of proteoglycans (PCs) from interleukin-1-(IL-1) treated articular cartilage expiants. The cartilage-bone marrow extract and the glycosaminoglycan-peptide complex (DAK-16) dose-dependently inhibited MMP proteoglycanases in vitro when tested at concentrations ranging from 0.5 to 55 mg/mL, displaying an IC 50 value of 31.78 mg/mL and 10.64 mg/mL (1.9 × 10 −4M) respectively. (R,S)-N-[2-[2-(hydroxyamino)-2-oxoethyl]-4methyl-1-oxopentyl]-L-leucyl -L-phenylalaninamide (U-24522) proved to be a potent inhibitor of MMP proteoglycanases (IC 50 value 1.8 × 10 −9M). None of the other tested drugs, such as possible chondroprotective drugs, nonsteroidal anti-inflammatory drugs (NSAIDs), disease modifying antirheumatic drugs (DMARDs), glucocorticoids and angiotensin-converting enzyme inhibitors tested at a concentration of 10 −4 M displayed any significant inhibition. Only U-24522, tested at a concentration ranging from 10 −4 to 10 −6 M, significantly inhibited the IL-1-induced augmentation of PG loss from cartilage expiants into the nutrient media, whereas DAK-16 and the cartilage-bone marrow extract were ineffective. DAK-16 and the cartilage-bone marrow extract did not modulate the IL-1-mediated reduced biosynthesis and aggregability of PGs by the cartilage expiants. The addition of 10 −5 M U-24522, however, partially maintained the aggregability of PGs ex vivo. In our experiments, both possible chondroprotective drugs as well as U-24522 demonstrated no cytotoxic effects on chondrocytes.