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Purpose: Based on demonstrated ERβ-selective transcriptional activity in a cellular model, it was hypothesized that in vivo, efficacious doses of the novel ERβ agonist OSU-ERβ-12 could be determined that have minimal activity in ERα-dependent tissues. These doses were hypothesized to have an anti-fibrotic effect in a Non-Alcoholic Steatohepatitis (NASH) liver disease model. Design: We used uterotrophic stimulation in an estrogen-naïve female mouse model to assess ERα activity. Briefly, groups of mice were administered doses of the ERβ selective agonist OSU-ERβ-12 and compared to a control ERβ-selective ligand, LY500307. The ERα effects of each ligand were characterized using bodyweight-normalized uterine tissue weights. Then doses of OSU-ERβ-12 were given to mice treated with 6 weeks of CCl4 to establish efficacy of OSU-ERβ-12 as an antifibrotic compound. Liver sections were stained with picrosirius red and the staining was then quantified using computer analysis. Results: OSU-ERβ-12 demonstrated ERβ-selective activity at doses <30 mg/kg, with 10 mg/kg being the highest selective dose. This dose was also efficacious at reducing the amount of fibrotic tissue picrosirius red staining seen in a liver section that was challenged with CCl4. LY500307 showed increased toxicity and decreased efficacy as compared to OSU-ERβ-12. Conclusions: Consistent with cellular activity data, uterotrophic stimulation data and the CCl4 challenge data suggest that 10 mg/kg doses of OSU-ERβ-12 are both ERβ-selective and efficacious in a CCl4 model of liver disease.