• Matrix metalloproteinases (MMPs) are enzymes which degrade molecules in the extracellular matrices (e.g., collagens, proteoglycans) of articular tissues of the TMJ. To date, four MMPs have been isolated from diseased human TMJs (MMP1, MMP2, MMP3, MMP9). These matrix degrading enzymes require zinc as a co-factor for activity. Tetracyclines inhibit these enzymes by chelation of zinc. Recent animal studies and limited clinical trials indicate that tetracyclines may limit progression of some degenerative TMJ diseases by inhibition of these matrix degrading enzymes. TNF and IL-1 are potent cytokines that have also been isolated from symptomatic human TMJs. These signaling molecules are believed to induce the synthesis of MMPs and other molecules that are involved in tissue degradation and inflammation. However, the activities of TNF and IL-1are not affected by tetracyclines. Cathepsin D is an intracellular endopeptidase that is involved in the intracellular degradation of molecules. Cathepsin D has been identified in synoviocytes of the TMJ. The activity of this enzyme is not affected by tetracyclines.