Tetracyclines inhibit connective tissue breakdown by multiple non-antimicrobial mechanisms

Adv Dent Res. 1998 Nov;12(2):12-26. doi: 10.1177/08959374980120010501.


A seminal experiment involving a germ-free rat model of connective tissue breakdown (followed soon thereafter by a series of in vitro studies) identified an unexpected non-antimicrobial property of tetracyclines (TCs). This ability of TCs to inhibit matrix metalloproteinases (MMPs) such as collagenase was found to reflect multiple direct and indirect mechanisms of action, and to be therapeutically useful in a variety of dental (e.g., adult periodontitis) and medical (e.g., arthritis, osteoporosis, cancer) diseases. The site on the TC molecule responsible for its MMP-inhibitory activity was identified which led to the development of a series of chemically modified non-antimicrobial analogs, called CMTs, which also have therapeutic potential but do not appear to induce antibiotic side-effects. Longitudinal double-blind studies on humans with adult periodontitis have demonstrated that a sub-antimicrobial dose of doxycycline (previously reported to suppress collagenase activity in the periodontal pocket) is safe and effective and has recently been approved by the FDA as an adjunct to scaling and root planing.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.
  • Review

MeSH terms

  • Animals
  • Anti-Bacterial Agents / pharmacology
  • Anti-Bacterial Agents / therapeutic use
  • Connective Tissue / drug effects*
  • Connective Tissue / enzymology
  • Doxycycline / pharmacology
  • Doxycycline / therapeutic use
  • Extracellular Matrix / enzymology
  • Humans
  • Matrix Metalloproteinase Inhibitors
  • Metalloendopeptidases / antagonists & inhibitors*
  • Periodontal Diseases / drug therapy*
  • Periodontal Diseases / enzymology*
  • Protease Inhibitors / pharmacology*
  • Protease Inhibitors / therapeutic use
  • Rats
  • Tetracyclines / chemistry
  • Tetracyclines / pharmacology*
  • Tetracyclines / therapeutic use


  • Anti-Bacterial Agents
  • Matrix Metalloproteinase Inhibitors
  • Protease Inhibitors
  • Tetracyclines
  • Metalloendopeptidases
  • Doxycycline