In vivo inhibition of human neutrophil collagenase (MMP-8) activity during long-term combination therapy of doxycycline and non-steroidal anti-inflammatory drugs (NSAID) in acute reactive arthritis

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Abstract
We studied the in vivo effect of long‐term doxycycline treatment combined with NSAID on human interstitial collagenases, other matrix melalloproteinases, serine proteinases, tissue inhibitor of matrix metalloproteinase‐1 (TIMP‐1) and lactoferrin from saliva and serum during the course of acute reactive arthritis (ReA). Collagenase activity and serine proteases (elastase‐like, cathepsin G‐like and trypsin‐like activities) of saliva (n= 10) and gelatinase, lactoferrin and TIMP‐1 of saliva (n=10) and serum (n= 10) samples before and after 2 months doxycycline treatment, combined with NSAID, were studied by quantitative SDS‐PAGE assay, ELISA assay and by spectrophotometric assay. The cellular source and molecular forms of salivary collagenase were characterized by immunoblotting using specific antisera. We found that activities of total and endogenously active interstitial collagenase reduced significantly. The salivary collagenase was found to originate from neutrophils. No fragmentation of either pro 75‐kD and active 65‐kD MMP‐8 was detected after 2 months doxycycline treatment. However, during 2 months doxycycline and NSAID treatment no reduction of salivary and serum gelatinase, lactoferrin and TIMP–1‐levels and salivary serine protease activities were detected. The in vivo inhibition of collagenase (MMP‐8) activity during long‐term doxycycline therapy in human saliva containing inflammatory exudate of ReA patients may contribute to the reduced tissue destruction observed in recent clinical and animal model studies in arthritides during long‐term doxycycline/tetracycline treatment.