Table 1.

Nonantibiotic tetracyclines as host modulators inhibit connective tissue breakdown: pleiotropic mechanisms of action^a

A. Extracellular mechanisms Direct inhibition of activated matrix metalloproteinases in connective tissues, dependent on Zn++ and Ca++ binding by nonantibiotic tetracyclines Inhibition of promatrix metalloproteinase activation by reactive oxygen species scavenging, independent of cation binding by nonantibiotic tetracyclines Inactivation (by partial proteolysis) of promatrix metalloproteinases, dependent on the binding of cations by nonantibiotic tetracyclines Indirect inhibition of serine proteinases (eg, elastase) by preventing the matrix metalloproteinase‐mediated breakdown of serum alpha1‐proteinase inhibitor (ie, alpha1‐PI, also known as alpha1‐antitrypsin)

B. Cellular mechanisms Decreased expression of inflammatory cytokines, nitric oxide, and phospholipase A2, thus suppressing promatrix metalloproteinase expression

C. Proanabolic effects “Upregulated” collagen synthesis, osteoblast activity, and bone formation

^aModified from Golub et al.2