PHARMACOLOGICAL EFFECT OF TETRACYCLINES ON PROTEOGLYCANASES FROM INTERLEUKIN-1-TREATED ARTICULAR-CARTILAGE

Based on previous in vivo and in situ studies showing that tetracyclin es possess antidegenerative effects on cartilage in conjunction with a reduced proteoglycan (PG) loss from the extracellular matrix, we inve stigated the effects of doxycycline, minocycline and tetracycline on t he degradation and biosynthesis of PGs by bovine articular cartilage e xplants, both in vitro and in situ. Doxycycline, minocycline and tetra cycline dose dependently, although weakly, inhibited PG degrading matr ix metalloproteinases (MMPs) in vitro, when tested at concentrations r anging from 1 to 100 mu M. Ro 31-4724 proved to be a potent inhibitor of MMP proteoglycanases (IC50 value 1.5 nM). Only at a concentration o f 100 mu M did doxycycline and minocycline significantly inhibit the i nterleukin-1 (IL-1)-induced augmentation of PG loss from cartilage exp lants into the nutrient media. The tetracyclines did not modulate the IL-1-mediated reduced aggregability of PGs, whereas 10 mu M Ro 31-4724 partially restored the aggregability of PGs ex vivo. Tetracycline eve n at this high concentration was ineffective. Compared to the effects of the MMP inhibitor Ro 31-4724, treatment with tetracyclines at thera peutic serum levels of 1 or 10 mu M was minimal, with little or no eff ect on cartilage proteoglycanases and PG biosynthesis. In our experime nts, tetracyclines and Ro 31-4724 at doses evaluated had no cytotoxic effects on chondrocytes. (C) 1998 Elsevier Science Inc.