title: Inhibition of alveolar bone loss by matrix metalloproteinase inhibitors in experimental periodontal disease.
abstract: 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.
authors.affiliation: Department of Oral Biology and Pathology, School of Dental Medicine, State University of New York at Stony Brook, USA.
authors.forename: Nungavaram S
authors.initials: NS
authors.lastname: Ramamurthy
authors.forename: Jing-wen
authors.initials: JW
authors.lastname: Xu
authors.forename: John
authors.initials: J
authors.lastname: Bird
authors.forename: Andrew
authors.initials: A
authors.lastname: Baxter
authors.forename: Ranjev
authors.initials: R
authors.lastname: Bhogal
authors.forename: Ruth
authors.initials: R
authors.lastname: Wills
authors.forename: Bob
authors.initials: B
authors.lastname: Watson
authors.forename: David
authors.initials: D
authors.lastname: Owen
authors.forename: Mark
authors.initials: M
authors.lastname: Wolff
authors.forename: Robert A
authors.initials: RA
authors.lastname: Greenwald
mesh_terms: D051722:ADAM Proteins; D000072198:ADAM17 Protein; D016301:Alveolar Bone Loss / Q000473:pathology / Q000517:prevention & control*; D000539:Alveolar Process / Q000473:pathology; D000818:Animals; D002352:Carrier Proteins / Q000008:administration & dosage / Q000627:therapeutic use; D002508:Cephalometry; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004731:Endotoxins / Q000009:adverse effects; D004926:Escherichia coli; D018093:Gelatinases / Q000037:antagonists & inhibitors; D005881:Gingiva / Q000187:drug effects / Q000201:enzymology; D006877:Hydroxamic Acids / Q000008:administration & dosage / Q000627:therapeutic use; D007375:Interleukin-1 / Q000032:analysis / Q000037:antagonists & inhibitors; D015850:Interleukin-6 / Q000032:analysis; D008070:Lipopolysaccharides / Q000009:adverse effects; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors; D008855:Microscopy, Electron, Scanning; D010518:Periodontitis / Q000150:complications*; D011480:Protease Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides / Q000008:administration & dosage / Q000627:therapeutic use; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000037:antagonists & inhibitors; D000093242:Interleukin-6 Inhibitors
chemical_list: D051722:ADAM Proteins; D000072198:ADAM17 Protein; D002352:Carrier Proteins; D004731:Endotoxins; D018093:Gelatinases; D006877:Hydroxamic Acids; D007375:Interleukin-1; D015850:Interleukin-6; D008070:Lipopolysaccharides; D061965:Matrix Metalloproteinase Inhibitors; D008666:Metalloendopeptidases; D011480:Protease Inhibitors; D013449:Sulfonamides; D014409:Tumor Necrosis Factor-alpha; D000093242:Interleukin-6 Inhibitors; C455461:CH1766; C455462:CH6631