Two classes of
enzymes play an important role in connective tissue breakdown during various inflammatory diseases:
serine proteinases and
matrix metalloproteinases (
MMPs).
Tetracyclines (TCs) exhibit important anti-inflammatory and
MMP-inhibitory properties that are unrelated to their antibacterial activities. Of the various TCs and their chemically modified NON-
antibiotic analogs (CMTs) tested in vitro and in vivo,
CMT-3 (6-demethyl-6-deoxy 4 de-dimethylamino tetracycline) has repeatedly been shown to be the most potent inhibitor of
MMP activity and
cytokine production. In addition to its anti-
MMP function, we have shown that among all CMTs,
CMT-3 is the only CMT that can also directly inhibit both the amidolytic activity of human
leukocyte elastase (HLE, a
serine proteinase) and the extracellular matrix degradation mediated by HLE. In addition,
CMT-3 has been found to reduce
leukocyte elastase activity in vivo in gingival extracts of rats with experimental
periodontal disease. Thus,
CMT-3 can inhibit pathologic connective tissue breakdown by (at least) two mechanisms: direct inhibition of neutral
proteinases (
elastase and
MMPs); and protecting their endogenous inhibitors, α(1)-PI and TIMPs, from being digested and inactivated by
MMPs and HLE, respectively. The pleiotropic properties of
CMT-3 including (but not limited to) inhibition of
serine proteinases,
MMPs, and
cytokines provide impressive therapeutic potential to reduce excessive connective tissue breakdown during various
pathologic processes including inflammatory diseases,
cancer metastasis and
metabolic bone diseases.