Inhibition of alveolar bone loss by matrix metalloproteinase inhibitors in exjreimental jreiodontal 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.

Comparative analysis of the expression of metalloproteases and their inhibitors in resected crohnʼs disease and complicated diverticular disease

“…Although tetracycline is an antibiotic agent, it is also an established broad-spectrum MMP inhibitor. 32,33 Thus, our results suggest that modulation of MMPs would provide an additional mechanism other than the antibacterial effect in the case of complicated diverticulitis. In the present study we also found, in general, greater percentages of expression of MMPs and lower percentages of expression of TIMPs in CD cases than in diverticulitis cases, both in inflamed samples as well as in noninflamed samples.…”

A Dominant Function of IKK/NF-κB Signaling in Global Lipopolysaccharide-induced Gene Expression

“…For example, IL-6 and TNF have also been reported to be regulated by AP-1, and matrix metalloproteinase family proteins are induced by inflammatory mediators through activation of AP-1 (9,19). In fact, several matrix metalloproteinases have been reported to be highly expressed in inflamed periodontal tissues and inhibition of their expression attenuated tissue destruction (44). Like AP-1, EGR family proteins are also involved in the transcriptional regulation of inflammatory mediators (45).…”

Osmotic pressure of gingiva in periodontitis: Correlation with gingival proinflammatory cytokine production and alveolar bone destruction

“…32e38 Although it was postulated that these methods are satisfactory in generating periodontal inflammation and/or alveolar bone loss, a localized LPS injection may be a more-controlled method, as repeated doses of this stimulant may induce more-predictable reactions in tissues. 39 LPS extracted from E. coli is a very potent endotoxin in tissue destruction, and it is widely used to create experimental periodontitis as a non-periodontopathogenic bacterial agent 25,39e42 because of its similar effects on the periodontium as the LPS of periodontopathogenic bacteria. 25,43 In the present study, we also used E. coli LPS to provoke periodontal tissue destruction by endotoxin induction.…”