Tetracyclines Inhibit Connective Tissue Breakdown: New Therapeutic Implications for an Old Family of Drugs

SAGE Publications - Tập 2 Số 3 - Trang 297-321 - 1991
Lorne M. Golub1, N S Ramamurthy1, T. F. McNamara1, Robert A. Greenwald2, Barry R. Rifkin3
1Department of Oral Biology and Pathology, School of Dental Medicine, State University of New York at Stony Brook, Stony Brook, New York
2Department of Medicine (Rheumatology), Long Island Jewish Medical Center, New Hyde Park, New York
3Department of Oral Medicine and Pathology, New York University School of Dentistry, New York, New York

Tóm tắt

Tetracyclines have long been considered useful adjuncts in peridontal therapy based on their antimicrobial efficacy against putative periodontopathogens. However, recently these drugs were found to inhibit mammalian collagenases and several other matrix metalloproteinases (MMPs) by a mechanism independent of their antimicrobial activity. Evidence is presented that this property may be therapeutically useful in retarding pathologic connective tissue breakdown, including bone resorption. The experiments leading to this discovery are described and possible mechanisms are addressed, including the specificity of tetracyclines' anti-collagenase activity, the role of the drugs' metal ion (Zn2+, Ca2+)- binding capacity, and the site on the tetracycline molecule responsible for this nonantimicrobial property. Of extreme interest, the tetracycline molecule has been chemically modified in multiple ways, generating a new family of compounds called CMTs (chemically modified tetracyclines) that lack antimicrobial but still retain anti-collagenase activity. The first of these CMTs, 4-de-dimethylaminotetracycline, was found not to produce a major side-effect of antimicrobial tetracycline therapy- its administration to experimental animals did not result in the emergence of tetracycline-resistant microorganisms in the oral flora and gut. Numerous examples of the clinical potential of this non-antimicrobial property of tetracyclines in the treatment of periodontal and several medical diseases (e.g., sterile corneal ulcers, rheumatoid arthritis, skin bullous lessions, tumor-induced angiogenesis and metastasis) are discussed.

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