Reactive oxygen species activate and tetracyclines inhibit rat osteoblast collagenase

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Abstract
Recent studies have demonstrated that tetracyclines (TCs) scavenge reactive oxygen species (ROS). Hypochlorous acid (HOCI), an ROS produced by neutrophils, has been shown to activate neutrophil procollagenase. The objective of the present study was to determine whether (1) HOCI also activated osteoblast procollagenase and (2) TCs inhibited this enzyme in the presence of HOCI. HOCI (5 μM) activated the proenzyme approximately sixfold (P < 0.01) from the medium of PTH‐treated UMR‐106–01 osteoblastic osteosarcoma cells as determined by functional collagenase assay (3H‐methyl‐labeled collagen substrate). Doxycycline (50–400 μM) and chemically modified tetracycline, CMT‐1 (100–400 μM), significantly inhibited collagenase activity 50–90% and 40–80%, respectively, in the presence of 5 μM HOCI. Concentrations of 6–25 μM doxycycline and 10–50 μM CMT‐1 had no significant effect. Furthermore, an excess concentration of cation (50 mM CaCI2 or 50 μM ZnCI2) added to the incubation mixtures containing either doxycycline or CMT‐1 did not restore collagenase activity, as demonstrated by SDS‐PAGE‐fluorography. These data suggested that TCs reduced available HOCI and thus prevented the hypochlorous acid conversion of the osteoblast proenzyme to active collagenase. TCs may have therapeutic potential in the treatment of periodontitis and other diseases by several mechanisms that inhibit pathologic collagen breakdown.
Funding Information
  • National Institute of Dental Research (DE-09576, R37DE-03987)