Previous studies suggest that salivary and pulp-derived host enzymes, matrix metalloproteinases (MMPs), may be involved in dentin caries pathogenesis. To study the inhibition of acid-activated human salivary MMPs by non-antimicrobial chemically modified tetracyclines (CMTs), we used a functional activity assay with 125I-labeled gelatin as a substrate. To address the role of MMPs in the progression of fissure caries in vivo, we administered the MMP inhibitors CMT-3 and zoledronate to young rats per os for 7 weeks, 5 days a week. Caries lesions were visualized by Schiff reagent in sagittally sectioned mandibular molars. Marked reduction in gelatinolytic activity of human salivary MMPs was observed with CMT-3. CMT-3 and zoledronate, both alone and in combination, also reduced dentin caries progression in the rats. These results suggest that MMPs have an important role in dentin caries pathogenesis, and that MMP inhibitors may prove to be useful in the prevention of caries progression.
Birkedal-Hansen H. (1995). Proteolytic remodeling of extracellular matrix . Curr Opin Cell Biol7:728-735.
2.
Boissier S., Ferreras M., Peyruchaud O, Magnetto S., Ebetino FH, Colombel M., et al. (2000). Bisphosphonates inhibit breast and prostate carcinoma cell invasion, an early event in the formation of bone metastases . Cancer Res60:2949-2954.
3.
Ciancio S., Ashley R. (1998). Safety and efficacy of sub-antimicrobial-dose doxycycline therapy in patients with adult periodontitis. Adv Dent Res12:27-31.
4.
Clarkson BH, Hall DL, Heilman JR, Wefel JS (1986). Effect of proteolytic enzymes on caries lesion formation in vitro. J Oral Pathol15:423-429.
5.
Dayan D., Binderman I., Mechanic GL (1983). A preliminary study of activation of collagenase in carious human dentine matrix. Arch Oral Biol28:185-187.
6.
Dung S.-Z, Gregory RL, Li Y., Stookey GK (1995). Effect of lactic acid and proteolytic enzymes on the release of organic matrix components from human root dentin. Caries Res29:483-489.
7.
Evans CE, Braidman IP (1994). Effects of two novel bisphosphonates on bone cells in vitro. Bone Miner26:95-107.
Golub LM, Ramamurthy NS, McNamara TF, Greenwald RA, Rifkin BR (1991). Tetracyclines inhibit connective tissue breakdown: new therapeutic implications for an old family of drugs. Crit Rev Oral Biol Med2:297-321.
10.
Golub LM, Lee H.-M, Ryan ME, Giannobile WV, Payne J., Sorsa T. (1998). Tetracyclines inhibit connective tissue breakdown by multiple non-antimicrobial mechanisms. Adv Dent Res12:12-26.
11.
Hietala EL, Tjaderhane L., Larmas M. (1993). Dentin caries recording with Schiffs reagent, fluorescence and backscattered electron image. J Dent Res72:1588-1592.
12.
Huumonen S., Pajari U., Backman T., Tjaderhane L., Larmas M. (1996). Effects of low-dose glucocorticoid treatment on dentin formation and dentinal caries in rats. Acta Odontol Scand54:282-286.
13.
Katz S., Park KK, Palenik CJ (1987). In-vitro root surface caries studies. J Oral Med42:40-48.
14.
Kawasaki K., Featherstone Jdb (1997). Effects of collagenase on root demineralization . J Dent Res76:588-595.
15.
Lauhio A., Salo T., Tjaderhane L., Lahdevirta J., Golub LM, Sorsa T. (1995). Tetracyclines in treatment of rheumatoid arthritis . Lancet346:645-646.
16.
Llano E., Pendas AM, Knauper V., Sorsa T., Salo T., Salido E., et al. (1997). Identification and structural and functional characterization of human enamelysin (MMP-20). Biochemistry36:15101-15108.
17.
Martin-De Las Heras S., Valenzuela A., Overall CM (2000). The matrix metalloproteinase gelatinase A in human dentine. Arch Oral Biol45:757-765.
18.
National Research Council (1972). Nutrient requirements of the laboratory rats. In: Committee on animal nutrition (editors). Nutrient requirements of laboratory animals . No. 10. 2nd ed. Washington, DC: National Academy of Science, pp. 56-93.
19.
Palosaari H., Wahlgren J., Larmas M., Ronka H., Sorsa T., Salo T., et al. (2000). The expression of MMP-8 in human odontoblasts and dental pulp cells is down-regulated by TGF-β1. J Dent Res79:77-84.
20.
Sorsa T., Ramamurthy NS, Vernillo AT, Zhang X., Konttinen YT, Rifkin BR, et al. (1998). Functional sites of chemically modified tetracyclines: inhibition of the oxidative activation of human neutrophil and chicken osteoclast pro-matrix metalloproteinases. J Rheumatol25:975-982.
21.
Teronen O, Heikkila P., Konttinen YT, Laitinen M., Salo T., Hanemaaijer R., et al. (1999). MMP inhibition and downregulation by bisphosphonates . Ann NYAcad Sci878:453-465.
22.
Tjaderhane L., Hietala EL, Larmas M. (1994). Reduction in dentine apposition in rat molars by a high-sucrose diet. Arch Oral Biol39:491-495.
23.
Tjaderhane L., Hietala EL, Svanberg M., Larmas M. (1995). Morphologic analysis of dentine formation in young rat molars during the recovery phase with calcium alone or combined with xylitol following a low-calcium regimen. Arch Oral Biol40:707-711.
24.
Tjaderhane L., Larjava H., Sorsa T., Uitto V.-J, Larmas M., Salo T. ( 1998a). The activation and function of host matrix metalloproteinases in dentin matrix breakdown in caries lesions. J Dent Res77:1622-1629.
25.
Tjaderhane L., Salo T., Larjava H., Larmas M., Overall CM (1998b). A novel organ culture method to study the function of human odontoblasts in vitro: gelatinase expression by odontoblasts is differentially regulated by TGF-β1. J Dent Res77:1486-1496.
26.
Tjaderhane L., Sulkala M., Sorsa T., Teronen O, Larmas M., Salo T. ( 1999). The effect of MMP inhibitor Metastat on fissure caries progression in rats. Ann NY Acad Sci878:686-688.
27.
Tjaderhane L., Palosaari H., Sulkala M., Wahlgren J., Larmas M., Bartlett JD, et al. (2000). Caries induces the expression of MMP-20 mRNA in human teeth (abstract). J Dent Res79(Spec Iss):344.
28.
Tjaderhane L., Palosaari H., Wahlgren J., Larmas M., Sorsa T., Salo T. ( 2001). Human odontoblast culture method: the expression of collagen and matrix metalloproteinases (MMPs). Adv Dent Res 15 (in press).
