ESR1 and Arthritis: To confirm the requirement of ERα for the ameliorating effects of E2 treatment on arthritis by using a genetically modified animal model, total ERα-/- and their corresponding WT littermates (experiment 2, see Materials and methods) were challenged with antigen according to the regimen illustrated in Figure 1A. E2 treatment significantly increased the uterus weight of WT littermates (805%, P <0.001), but not total ERα-/- mice, compared with placebo.