Inhibition of epithelial cell matrix metalloproteinases by tetracyclines

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Abstract
The effects of tetracyclines on periodontal epithelial cells were investigated by culturing cells from porcine rests of Malassez in the presence of oxytetracycline, doxycycline or one of two analogues of tetracycline bearing no antimicrobial activity. Matrix metalloproteinase activity produced by the epithelial cells was assayed by quantitation of radioactive gelatin degradation and by gelatin enzymography. The results show that all tested tetracyclines exerted a direct dose-dependent inhibitory effect on epithelial cell gelatinases. Furthermore, epithelial cells cultured with doxycycline, oxytetracycline and de-dimethylaminotetracycline in concentrations ranging from 1 to 50 micrograms/ml showed a marked reduction in secreted gelatinase activity when grown in alpha minimum essential medium in the absence of fetal calf serum. Viability of cells following this treatment, measured as lactate dehydrogenase activity released to the cell media, was not affected by the presence of any of these drugs at the concentrations used. Scanning electron microscopy revealed striking morphologic changes of the cells following treatment with tetracyclines in the absence of serum which include rounding, decreased intracellular contacts and increased intercellular spaces. No such effects were seen in cells cultured in the presence of serum. These results provide evidence that periodontal epithelial cells produce matrix metalloproteinases whose activities are inhibited by tetracyclines and their non-antimicrobial analogues at concentrations present in gingival crevicular fluid following tetracycline therapy. When used as adjuncts in periodontal therapy, tetracyclines may therefore inhibit epithelial cell mediated degradation of basement membrane and subepithelial connective tissue.