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Notes: Recently, a new mechanism was proposed to explain the therapeutic efficacy of tetracyclines in periodontal disease— that specifically these antibiotics directly inhibit the activity of collagenase (and possibly other collagenolytic enzymes) produced by the host tissues resulting in a reduced rate of collagen breakdown (Golub et al. 1983). In the current studies, the effect of tetracyclines (minocycline, doxycycline, tetracycline) on collagenolytic enzyme activity was examined in human periodontal pockets and in several animal systems. In the clinical studies, gingival crevicular fluid (GCF) was collected on filter paper strips from individual periodontal pockets, the volume measured with the Periotron 6000, and the Gingival Index and pocket depth scored immediately thereafter at the same sites. The strips were incubated with [3H-methyi] collagen maintained in solution (or with 14C-glycine labeled collagen Fibrils), and the radiolabeled collagen degradation products measured in a liquid scintillation spectrometer, Using the techniques of SDS-PAGE and fluorography, the GCF was observed to generate collagen degradation products characteristic of those produced by mammalian collagenase, a finding consistent with previous studies. Both minocycline and tetracycline therapy reduced GCF collagenolytic activity about 70% during the initial weeks of treatment; the clinical parameters also showed improvements at the same time periods. This reduction in collagenolytic activity had largely regressed by 5 weeks after terminating tetracycline therapy and by 19 weeks after minocycline therapy, in the absence of other forms of periodontal treatment. In a preliminary study, 50 days of doxycycline treatment also reduced GCF collagenase activity, an effect which persisted for at least 2 months (but less than 1 year) after terminating its administration. In several studies involving experimental animals, the tetracyclines (1) in vivo, were found to reduce the pathologically excessive collagenase activity in gingiva and skin of diabetic rats; and (2) in vitro, directly inhibited the activity of collagenases from rat PMNL's and rabbit chondrocytes. The data in the current and our previous studies (Golub et al. 1983, Gomes, Golub & Ramamurthy 1984) continue to support the hypothesis that tetracyclines, by directly inhibiting collagenolytic enzyme(s) activity, may be therapeutically useful in treating diseases, such as periodontitis, characterized by excessive collagen breakdown.