Periodontal disease is characterized by excessive host
collagenase resulting in loss of gingival and periodontal ligament
collagen and adjacent alveolar bone. Intragingival
endotoxin injection induces a model of
periodontal disease characterized by rapid bone loss with biochemical features similar to that of naturally occurring
adult periodontitis.
CH1766, a
peptide with a
zinc binding moeity which fits into the active site of the
enzyme, and
CH6631, a
hydroxamic acid derivative with aryl-substituted sulphonamide residues, are inhibitors of
matrix metalloproteinases (MMPIs) with differing inhibitory profiles as characterized by in vitro assays. In this study,
endotoxin was injected into the gingivae of rats which were then treated orally with either 3 mg/kg or 30 mg/kg of one of the two inhibitory compounds. The gingival tissues were assessed for
collagenase and
gelatinase activity, plus three different pro-inflammatory
cytokines. In addition, alveolar bone height in defleshed jaws was studied by computerized morphometric analysis and scanning electron microscopy. Both drugs reduced active and/or total
MMP activity, in many cases to normal, and also partially normalized
cytokine levels as well. A dose-response effect was seen with regard to amelioration of
lipopolysaccharide-induced
alveolar bone loss with both drugs. Other than studies with
tetracyclines, this is the first report of beneficial effects of MMPIs in a model of
periodontal disease, strongly suggesting that this class of agents could bring therapeutic benefit to patients with this disorder, and that
periodontal disease can be used as a model to demonstrate in vivo efficacy of this class of drugs.