BLOCKING PERIODONTAL-DISEASE PROGRESSION BY INHIBITING TISSUE-DESTRUCTIVE ENZYMES - A POTENTIAL THERAPEUTIC ROLE FOR TETRACYCLINES AND THEIR CHEMICALLY-MODIFIED ANALOGS

TETRACYCLINES (TCs) HAVE WIDE THERAPEUTIC usage as antimicrobial agent s; these drugs (e.g., minocycline, doxycycline) remain useful as adjun cts in periodontal therapy. However, TCs also have non-antimicrobial p roperties which appear to modulate host response. In that regard, TCs and their chemically-modified analogs (CMTs) have been shown to inhibi t the activity of the matrix metalloproteinase (MMP), collagenase. The activity of this enzyme appears crucial in the destruction of the maj or structural protein of connective tissues, collagen. Such pathologic collagenolysis may be a common denominator in tissue destructive dise ases such as rheumatoid and osteoarthritis, diabetes mellitus, bullous dermatologic diseases, corneal ulcers, and periodontitis. The mechani sms 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 inv estigation including the following: TCs may 1) directly inhibit the ac tivity of extracellular collagenase and other MMPs such as gelatinase; 2) prevent the activation of its proenzyme by scavenging reactive oxy gen 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 struc ture and function. Several recent studies have also addressed the ther apeutic potential of TCs and CMTs in periodontal disease. These drugs reduced excessive gingival collagenase activity and severity of period ontal breakdown in rats infected with Porphyromonas gingivalis and in diabetic rats. Furthermore, the latter drug (CMT) was not associated w ith the emergence of TC-resistant microorganisms. In human clinical tr ials, low-dose doxycycline therapy substantially reduced collagenase a ctivity in the gingiva and GCF, and prevented the loss of attachment i n adult periodontitis. Clearly, the non-antimicrobial properties of TC s have enormous medical and dental therapeutic potential since these d rugs can inhibit the activity of MMPs and their degradation of non-oss eous and osseous connective tissues.