Blocking Periodontal Disease Progression by Inhibiting Tissue‐Destructive Enzymes: A Potential Therapeutic Role for Tetracyclines and Their Chemically‐Modified Analogs

Abstract

Tetracyclines (TCs) have wide therapeutic usage as antimicrobial agents; these drugs (e.g., minocycline, doxycycline) remain useful as adjuncts in periodontal therapy. However, TCs also have non-antimicrobial properties which appear to modulate host response. In that regard, TCs and their chemically-modified analogs (CMTs) have been shown to inhibit the activity of the matrix metalloproteinase (MMP), collagenase. The activity of this enzyme appears crucial in the destruction of the major structural protein of connective tissues, collagen. Such pathologic collagenolysis may be a common denominator in tissue destructive diseases such as rheumatoid and osteoarthritis, diabetes mellitus, bullous dermatologic diseases, corneal ulcers, and periodontitis. The mechanisms by which TCs affect and, possibly, diminish bone resorption (a key event in the pathogenesis of periodontal and other diseases) are not yet understood. However, a number of possibilities remain open for investigation including the following: TCs may 1) directly inhibit the activity of extracellular collagenase and other MMPs such as gelatinase; 2) prevent the activation of its proenzyme by scavenging reactive oxygen species generated by other cell types (e.g. PMNs, osteoclasts); 3) inhibit the secretion of other collagenolytic enzymes (i.e. lysosomal cathepsins); and 4) directly affect other aspects of osteoclast structure and function. Several recent studies have also addressed the therapeutic potential of TCs and CMTs in periodontal disease. These drugs reduced excessive gingival collagenase activity and severity of periodontal breakdown in rats infected with Porphyromonas gingivalis and in diabetic rats. Furthermore, the latter drug (CMT) was not associated with the emergence of TC-resistant microorganisms.(ABSTRACT TRUNCATED AT 250 WORDS)

Antimicrobial Activity of Minocycline-Loaded Genipin-Crosslinked Nano-Fibrous Chitosan Mats for Guided Tissue Regeneration

“…The ability of the membranes to prevent infection through the local delivery of antibiotics during bone healing of the site while also preventing soft tissue penetration may lead to a significant improvement in clinical bone healing in patients. Minocycline is commonly used in periodontal therapy as an antimicrobial agent but it also has the ability to limit tissue destruction, by inhibition of tissue destroying enzymes such as collagenase, MMP-2 and MMP-9 [13].…”

Interleukin-6 Released from Fibroblasts Is Essential for Up-regulation of Matrix Metalloproteinase-1 Expression by U937 Macrophages in Coculture

“…Matrix metalloproteinases (MMPs), 3 a family of proteolytic enzymes that degrade collagen and other matrix proteins including elastin, fibronectin, proteoglycan, and laminin, play an essential role in the periodontal tissue destruction (4,5). MMPs are expressed in inflamed periodontal tissue by inflammatory cells including monocytes, macrophages, lymphocytes, and polymorphonuclear cells and also by resident cells such as fibroblasts, epithelial cells, and endothelial cells (6,7).…”

Iron-Chelating Activity of Tetracyclines and Its Impact on the Susceptibility of Actinobacillus actinomycetemcomitans to These Antibiotics

“…Several studies have shown that tetracyclines are active against A. actinomycetemcomitans (15,17,23). Tetracyclines are extensively used as adjuncts in the treatment of periodontitis, a disease affecting the tooth-supporting tissues (gingiva, periodontal ligament, and alveolar bone) and resulting in tooth loss (21,23). The beneficial effect of tetracyclines relates to three distinctive characteristics: (i) efficiency in suppressing growth of periodontopathogenic gram-negative anaerobic bacteria, (ii) capacity to reach high concentrations in the gingival crevicular fluid, and (iii) capacity to extend their antimicrobial effect by binding to the tooth surface and being slowly released in the periodontal pocket in an active form (23).…”