ANTI-COLLAGENOLYTIC MECHANISM OF ACTION OF DOXYCYCLINE TREATMENT IN RHEUMATOID-ARTHRITIS

Tetracyclines exert, independently of their antimicrobial activity, an ti-collagenolytic effects by inhibiting activities of human interstiti al collagenases and by preventing the oxidative activation of latent p ro-collagenases. We tested the clinical response to a 3-month doxycycl ine in concert with collagenase activity in 12 rheumatoid arthritis (R A) patients. Patients received 150 mg/day of doxycycline for 3 months. Clinical assessments at zero, six and 12 weeks comprised classificati on of the functional class, joint score index, Hb, CRP, ESR, health as sessment questionnaire, visual analogue scale (VAS) of pain, pain disa bility index, comprehensible psychopathological rating scale (CPRS), S DS-PAGE laser densitometric collagenase activity measurements and West ern blots. Significant reductions were seen in joint score index (P<0. 01), pain VAS (P<0.05) and some CPRS parameters. Furthermore, collagen ase activities measured from saliva by quantitative SDS-PAGE electroph oresis were significantly reduced during the 12-week intervention (P<0 .01). Western blots demonstrated intact 75-80 kDa enzyme protein (clas sic neutrophil collagenase), but also a newly discovered mesenchymal, less glycosylated 40-55 kDa MMP-8 subtype of fibroblast/chondrocytic o rigin. These results indicate that the documented favourable clinical response may in part be due to in vivo inhibition of classic neutrophi l and mesenchymal collagenase/MMP-8 activities produced by doxycycline . This anti-collagenolytic doxycycline effects is mediated through inh ibition of the enzyme activity and not through degradation of the enzy me, which may have contributed to the reportedly reduced tissue destru ction, as has been seen in clinical studies concerning RA as well as r eactive arthritis.