Enhancement of Collagen-induced Arthritis in Female Mice by Estrogen Receptor Blockage

Objective: To determine whether estrogen-mediated suppression of collagen-induced arthritis (CIA) in mice acts via the nuclear estrogen receptors (ERs).

Methods: CIA was induced in noncastrated normal (B10.Q x DBA/1)F1 (QD) female mice. The mice were treated with the ER antagonist ICI 182,780, which binds to both ERalpha and ERbeta, either on days 2, 6, 10, and 14 or on days 14, 18, 22, and 26 after type II collagen (CII) immunization. The effects of treatment and development of arthritis were correlated with the estrus cycle by inspection of vaginal smears (VS). By a combination of treatments with both estriol (E3) and ICI 182,780 during the time of expected onset of CIA in castrated QD female mice, the protective effect of E3 in CIA was analyzed.

Results: Treatment with ICI 182,780 of QD female mice immunized with CII triggered an earlier onset of arthritis during the period when the estrus cycle was blocked. The arthritis-modulating effect of ICI 182,780 was even obtained at doses that were insufficient to block estrus cycling, as observed in the VS response. E3 is an estrogen with low estrogenic potency but with a relatively potent antiarthritis effect. Doses of ICI 182,780 that were suboptimal for blocking estrus cycling blocked the E3-mediated suppression of CIA in castrated female mice.

Conclusion: These findings show that estrogen-induced suppression of CIA is mediated via the nuclear ERs and is operating at physiologic, possibly even subphysiologic, levels of estrogens.