Tetracycline Inhibition and the Cellular Source of Collagenase in Gingival Crevicular Fluid in Different Periodontal Diseases. A Review Article

Abstract

Tetracyclines have recently been shown to inhibit the activity of some but not all mammalian matrix metalloproteinases believed to mediate periodontal destruction. However, the specificity of this effect, which could have significant therapeutic implications for different periodontal diseases, has not been examined in detail. Doxycycline and 4de‐dimethylaminotetracycline (CMT‐1) have been tested in vitro for their ability to inhibit human neutrophil and fibroblast interstitial collagenases and collagenase in human gingival crevicular fluid (GCF). The GCF samples were obtained from systemically healthy and insulin‐dependent diabetic adult Periodontitis patients and from localized juvenile Periodontitis (UP) patients. The concentrations of these 2 tetracyclines required to inhibit 50% of the collagenase activity (IC50) were found to be 15 to 30 μM for human neutrophil collagenase and for collagenase in GCF of systemically healthy and diabetic adult Periodontitis patients. These concentrations approximate the tetracycline levels observed in vivo during treatment with these drugs. In contrast, human fibroblast collagenase and GCF collagenase from UP patients were both relatively resistant to tetracycline inhibition; the IC50 for doxycycline and CMT‐1 for these 2 sources of collagenase were 280 and 500 μM, respectively. Based on these and other findings, we propose the following: 1) that systemic levels of tetracycline may inhibit connective tissue breakdown by inhibiting neutrophil collagenase; 2) that tetracyclines do not inhibit fibroblast‐type collagenase, which may help explain their lack of effect on normal connective tissue remodeling; 3) that tetracycline inhibition of collagenases may serve to identify the cellular origin of the enzyme; and 4) that tetracyclines can also prevent the oxidative activation of latent human procollagenases. With regards to therapy, the anti‐collagenase property of tetracyclines may be an effective adjunct in targeting tissue breakdown in systemically healthy and diabetic adult Periodontitis patients. However, in juvenile Periodontitis the anticollagenase property of tetracyclines may be less important than the antimicrobial activity of the drug because of the relative resistance of fibroblast‐type collagenase to tetracycline inhibition. J Periodontol 1993; 64:82–88.

Doxycycline disrupts chondrocyte differentiation and inhibits cartilage matrix degradation

“…Doxycycline has been previously shown to inhibit purified metalloproteinases, including interstitial collagenase from fibroblasts (24), neutrophil collagenase (25), and cartilage gelatinase (26). The dosage of doxycycline used in this study (83 FM, 41 M, and 10 pA4) is comparable with the drug concentrations reported by other investigators to inhibit enzyme activity of neutrophil collagenase but not fibroblast collagenase (27).…”

Reduction of matrix metalloproteinase 8-neutrophil collagenase levels during long-term doxycycline treatment of reactive arthritis

“…Tetracyclines can, independent of the drugs' antimicrobial efficacy, directly inhibit in vitro the activities of human interstitial collagenases and other MMPs (4, 6), especially preferring neutrophil collagenase (matrix metalloproteinase 8 [MMP-8]) (14), and, further, prevent oxidative activation of the latent procollagenases (8,12). Recent data suggest that the members of the tetracycline family of antibiotics can reduce tissue destruction events in arthritides (2,4,6,7,17). In a recent randomized, double-blind, placebo-controlled study it was found that a 3-month lymecycline (tetracycline-L-methylenelysine, a form of tetracycline) treatment significantly reduced the duration of Chlamydia trachomatis-induced reactive arthritis (ReA) (7).…”

“…Also, Greenwald et al recently administered chemically modified, nonantimicrobial but anticollagenolytic tetracyline (CMT) plus flurbiprofen to rats with adjuvant arthritis; combined therapy with CMT and NSAID resulted in significant reduction in bone erosion (5). It is of interest that doxycycline is a more efficient direct inhibitor of interstitial collagenases than minocycline or tetracycline (4,6,14). Thus, in regard to anticollagenolytic or antiproteolytic therapeutic action of tetracyclines, it appears to be most favorable to combine doxycycline with NSAIDs.…”

Odontogenic keratocysts/keratocystic odontogenic tumours: biological characteristics, clinical manifestation and treatment

“…This avoids single, rapid resorbtion of homologous material but rather its gradual replacement by autologous newly formed bone. Tetracycline inhibits the oxidative activity of latent procollagenase and has anti-inflammatory properties, which underscores its role in the reparative phase of healing the defect [47][48][49] . Experience with augmenting postoperative bone defects of jaw bone was published by Pazdera et al 46 and Zboril et al 50 .…”