This research program has identified: (i) diabetes-induced alterations in collagen metabolism including enhanced gingival (& skin) collagenolytic activity, and (ii) a new property of tetracycline - the ability to inhibit excess mammalian collagenase activity and collagen breakdown such as that seen during experimental diabetes. The application's specific aims, which now focus on the consequences of and mechanisms involved in the chemotherapeutic inhibition of pathologically-excessive collagenolysis, are as follows: (1) To determine whether tetracyclines inhibit tissue-destructive enzymes in addition to collagenase. Tetracyclines will be administerd to humans with chronic periodontitis and to rats with experimentally-induced gingival inflammation or diabetes and the drugs' effect on the activity of different enzymes such as elastase will be determined. Tetracyclines will also be incubated with these enzymes in vitro to identify possible direct effects on their activity; in some experiments, H3-tetracycline will be used to test for enzyme binding. (2) To determine whether tetracycline, when chemically- modified to eliminate its antibiotic efficacy, retains its anticollagenolytic properties. The modified drug will be tested in vivo, for example on diabetic rats which exhibit excess collagenase activity, and in vitro, on proteolytic enzyme activity and on bone undergoing resorption. (3) To determine whether tetracycline administration affects intracellular aspects of collagen metabolism such as alpha-chain hydroxylation and collagen production. Drug regimens known to be anticollagenolytic will be administerd to non-diabetic and diabetic rats and the incorporation of injected H3-proline into newly synthesized collagen (as H3-hydroxyproline) will be measured using newer techniques such as """"""""pool-expansion."""""""" (4) To determine whether chemically-modified tetracycline, which retains its anti-collagenase but not its antibiotic properties, can reduce the severity of microbially-induced periodontal destruction. Germfree rats will be monoinfected with Bacteroides gingivalis and gingival collagenase activity, gingival collagen content, alveolar bone loss, and the presence of the infecting organism will be monitored. The long-term objective is to use tetracyclines (including their non-antibiotic analogues) as probes of the role of collagenase in tissue breakdown during periodontal and other diseases and to develop pharmaco- therapeutic approaches to control pathologic collagenolysis.
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