title: Tetracyclines suppress matrix metalloproteinase activity in adjuvant arthritis and in combination with flurbiprofen, ameliorate bone damage.
abstract: Tetracyclines are potent inhibitors of 2 major matrix metalloproteinases which have been implicated in connective tissue degradation: collagenase and Type IV collagenase/gelatinase. We directly identified these enzyme activities in extracts of inflamed paw tissue from rats with adjuvant arthritis. Oral tetracycline therapy suppressed metalloproteinase activity in arthritic tissue, but even very high doses failed to exhibit substantial antiinflammatory efficacy (reduced joint swelling and paw diameter). Flurbiprofen, a conventional nonsteroidal antiinflammatory drug, reduced inflammatory indices as expected. The combination of the 2 agents administered orally completely inhibited collagenase activity, significantly inhibited gelatinase activity and produced substantial normalization of radiographic joint damage, far greater than either drug alone. Tetracycline inhibition curves in vitro suggest that the collagenase in this tissue is not of fibroblast origin. Tetracycline derivatives might be useful adjuncts to prevention of tissue damage in chronic inflammatory arthritides.
authors.affiliation: Department of Medicine, Long Island Jewish Medical Center, New Hyde Park, NY 11042.
authors.forename: R A
authors.initials: RA
authors.lastname: Greenwald
authors.forename: S A
authors.initials: SA
authors.lastname: Moak
authors.forename: N S
authors.initials: NS
authors.lastname: Ramamurthy
authors.forename: L M
authors.initials: LM
authors.lastname: Golub
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001169:Arthritis, Experimental / Q000201:enzymology*; D001842:Bone and Bones / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D002358:Cartilage, Articular / Q000201:enzymology; D017364:Collagenases / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004318:Doxycycline / Q000494:pharmacology; D004359:Drug Therapy, Combination; D004591:Electrophoresis, Polyacrylamide Gel; D005109:Extracellular Matrix / Q000187:drug effects / Q000201:enzymology*; D005480:Flurbiprofen / Q000008:administration & dosage / Q000494:pharmacology*; D020780:Matrix Metalloproteinase 9; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D008911:Minocycline / Q000494:pharmacology; D051381:Rats; D013752:Tetracycline / Q000494:pharmacology; D013754:Tetracyclines / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D013754:Tetracyclines; C053450:4-des-dimethylaminotetracycline; D005480:Flurbiprofen; D017364:Collagenases; D008666:Metalloendopeptidases; D020780:Matrix Metalloproteinase 9; D013752:Tetracycline; D008911:Minocycline; D004318:Doxycycline