Tetracyclines exert, independently of their antimicrobial activity, anti-collagenolytic effects by inhibiting activities of human interstitial
collagenases and by preventing the oxidative activation of latent pro-
collagenases. We tested the clinical response to a 3-month
doxycycline in concert with
collagenase activity in 12
rheumatoid arthritis (RA) patients. Patients received 150 mg/day of
doxycycline for 3 months. Clinical assessments at zero, six and 12 weeks comprised classification of the functional class, joint score index, Hb, CRP, ESR, health assessment questionnaire, visual analogue scale (VAS) of
pain,
pain disability index, comprehensible psychopathological rating scale (CPRS), SDS-PAGE
laser densitometric
collagenase activity measurements and Western blots. Significant reductions were seen in joint score index (P < 0.01),
pain VAS (P < 0.05) and some CPRS parameters. Furthermore,
collagenase activities measured from saliva by quantitative SDS-PAGE electrophoresis were significantly reduced during the 12-week intervention (P < 0.01). Western blots demonstrated intact 75-80 kDa
enzyme protein (classic
neutrophil collagenase), but also a newly discovered mesenchymal, less glycosylated 40-55 kDa MMP-8 subtype of fibroblast/chondrocytic origin. These results indicate that the documented favourable clinical response may in part be due to in vivo inhibition of classic neutrophil and mesenchymal
collagenase/
MMP-8 activities produced by
doxycycline. This anti-collagenolytic
doxycycline effects is mediated through inhibition of the
enzyme activity and not through degradation of the
enzyme, which may have contributed to the reportedly reduced tissue destruction, as has been seen in clinical studies concerning RA as well as
reactive arthritis.