Pharmacological effect of tetracyclines on proteoglycanases from interleukin-1-treated articular cartilage.
Based on previous in vivo and in situ studies showing that tetracyclines possess antidegenerative effects on cartilage in conjunction with a reduced proteoglycan (PG) loss from the extracellular matrix, we investigated the effects of doxycycline, minocycline and tetracycline on the degradation and biosynthesis of PGs by bovine articular cartilage explants, both in vitro and in situ. Doxycycline, minocycline and tetracycline dose dependently, although weakly, inhibited PG degrading matrix metalloproteinases (MMPs) in vitro, when tested at concentrations ranging from 1 to 100 microM. Ro 31-4724 proved to be a potent inhibitor of MMP proteoglycanases (IC50 value 1.5 nM). Only at a concentration of 100 microM did doxycycline and minocycline significantly inhibit the interleukin-1 (IL-1)-induced augmentation of PG loss from cartilage explants into the nutrient media. The tetracyclines did not modulate the IL-1-mediated reduced aggregability of PGs, whereas 10 microM Ro 31-4724 partially restored the aggregability of PGs ex vivo. Tetracycline even at this high concentration was ineffective. Compared to the effects of the MMP inhibitor Ro 31-4724, treatment with tetracyclines at therapeutic serum levels of 1 or 10 microM was minimal, with little or no effect on cartilage proteoglycanases and PG biosynthesis. In our experiments, tetracyclines and Ro 31-4724 at doses evaluated had no cytotoxic effects on chondrocytes.
Steinmeyer
J
J
Institute for Pharmacology and Toxicology, Rheinische Friedrich-Wilhelms-Universität Bonn, Germany.
Daufeldt
S
S
Taiwo
Y O
YO
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D002358:Cartilage, Articular / Q000187:drug effects* / Q000201:enzymology* / Q000378:metabolism; D002417:Cattle; D002470:Cell Survival / Q000187:drug effects; D046508:Culture Techniques; D004318:Doxycycline / Q000494:pharmacology; D004347:Drug Interactions; D007375:Interleukin-1 / Q000494:pharmacology*; D008666:Metalloendopeptidases / Q000187:drug effects* / Q000378:metabolism*; D008911:Minocycline / Q000494:pharmacology; D011509:Proteoglycans / Q000096:biosynthesis / Q000378:metabolism*; D013752:Tetracycline / Q000494:pharmacology
D000900:Anti-Bacterial Agents; D007375:Interleukin-1; D011509:Proteoglycans; C022474:proteoglycan-degrading metalloendopeptidases; D008666:Metalloendopeptidases; D013752:Tetracycline; D008911:Minocycline; D004318:Doxycycline