Inhibition of alveolar bone loss by matrix metalloproteinase inhibitors in experimental periodontal disease

被引:44
作者
Ramamurthy, NS
Xu, JW
Bird, J
Baxter, A
Bhogal, R
Wills, R
Watson, B
Owen, D
Wolff, M
Greenwald, RA
机构
[1] SUNY Stony Brook, Sch Dent Med, Dept Oral Biol & Pathol, Stony Brook, NY 11794 USA
[2] Long Isl Jewish Med Ctr, Div Rheumatol, New Hyde Pk, NY 11042 USA
[3] Celltech Chirosci Ltd, Cambridge, England
关键词
collagenase; periodontal disease; alveolar bone; cytokine; matrix; metalloproteinase;
D O I
10.1034/j.1600-0765.2002.00342.x
中图分类号
R78 [口腔科学];
学科分类号
1003 ;
摘要
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.
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页码:1 / 7
页数:7
相关论文
共 27 条
[1]   Clinical trials of a matrix metalloproteinase inhibitor in human periodontal disease [J].
Ashley, RA .
INHIBITION OF MATRIX METALLOPROTEINASES: THERAPEUTIC APPLICATIONS, 1999, 878 :335-346
[2]   Treatment with subantimicrobial dose doxycycline improves the efficacy of scaling and root planing in patients with adult periodontitis [J].
Caton, JG ;
Ciancio, SG ;
Blieden, TM ;
Bradshaw, M ;
Crout, RJ ;
Hefti, AF ;
Massaro, JM ;
Polson, AM ;
Thomas, J ;
Walker, C .
JOURNAL OF PERIODONTOLOGY, 2000, 71 (04) :521-532
[3]  
Chang KM, 1996, RES COMMUN MOL PATH, V91, P303
[4]  
Golub L M, 1998, Adv Dent Res, V12, P12
[5]  
Golub L M, 1992, Curr Opin Dent, V2, P80
[6]   FURTHER EVIDENCE THAT TETRACYCLINES INHIBIT COLLAGENASE ACTIVITY IN HUMAN CREVICULAR FLUID AND FROM OTHER MAMMALIAN SOURCES [J].
GOLUB, LM ;
WOLFF, M ;
LEE, HM ;
MCNAMARA, TF ;
RAMAMURTHY, NS ;
ZAMBON, J ;
CIANCIO, S .
JOURNAL OF PERIODONTAL RESEARCH, 1985, 20 (01) :12-23
[7]   A matrix metalloproteinase inhibitor reduces bone-type collagen degradation fragments and specific collagenases in gingival crevicular fluid during adult periodontitis [J].
Golub, LM ;
Lee, HM ;
Greenwald, RA ;
Ryan, ME ;
Sorsa, T ;
Salo, T ;
Giannobile, WV .
INFLAMMATION RESEARCH, 1997, 46 (08) :310-319
[8]   TETRACYCLINES INHIBIT CONNECTIVE-TISSUE BREAKDOWN - NEW THERAPEUTIC IMPLICATIONS FOR AN OLD FAMILY OF DRUGS [J].
GOLUB, LM ;
RAMAMURTHY, NS ;
MCNAMARA, TF ;
GREENWALD, RA ;
RIFKIN, BR .
CRITICAL REVIEWS IN ORAL BIOLOGY AND MEDICINE, 1991, 2 (03) :297-322
[9]   A NONANTIMICROBIAL TETRACYCLINE INHIBITS GINGIVAL MATRIX METALLOPROTEINASES AND BONE LOSS IN PORPHYROMONAS GINGIVALIS-INDUCED PERIODONTITIS IN RATS [J].
GOLUB, LM ;
EVANS, RT ;
MCNAMARA, TF ;
LEE, HM ;
RAMAMURTHY, NS .
INHIBITION OF MATRIX METALLOPROTEINASES: THERAPEUTIC POTENTIAL, 1994, 732 :96-111
[10]  
Greenwald RA, 1999, J RHEUMATOL, V26, P1650