A SELECTIVE ESTROGEN RECEPTOR ALPHA AGONIST (ORG 37663) SUPPRESSES INFLAMMATION AND ARTHRITIS IN MOUSE MODELS

Background: Estrogens have been studied for their effects on the immune system. Estrogens bind to both estrogen receptor α and β (ERα and ERβ). Estrogen receptor-mediated immune suppression has been demonstrated in animal models of autoimmune disease.Objectives: We studied the contribution of ERα and ERβ to estrogen-mediated suppression in a Tetanus Toxoid (TT) specific Delayed Type Hypersensitivity mouse model (TT-DTH) and in the mouse collagen-induced arthritis (CIA) model using Ethinyl Estradiol (EE, binds both ERα and ERβ) and ERα selective (Org 37663) and an ERβ selective (ERB-041) agonist.Methods: Transfected CHO cells were used to determine the preference of selected estrogens for ERα and/or ERβ binding. To asses the effect on a TT-DTH response, mice (ERα(-/-), ERβ(-/-) and WT) were daily treated (either s.c. or orally) with EE, ERB-041, Org 37663 or the glucocorticoid receptor agonist dexamethasone. Animals were immunized with Tetanus Toxoid (TT) in DDA on day 0, and challenged with TT on day 7. Twenty-four hours later footpad thickness was measured. At autopsy (forty eight hours later), the ERα sensitive uterus was weighed. In addition, DBA/1J mice were immunized and boosted with collagen type II. Treatment of arthritic mice with ER-selective compounds started when the disease was established. Arthritis was scored visually. Joint pathology was evaluated by histology, radiology, serum cartilage oligomeric matrix protein (COMP) levels and cytokine production in the joint. Dynamics of bone metabolism was measured using osteocalcin (bone formation) and CTX-I (bone destruction) ELISA.Results: Agonist transactivation experiments in vitro showed that Org 37663 had a preference for ERα, ERB-041 had a preference for ERβ whereas Ethinyl Estradiol (EE) was found to transactivate both ERα and ERβ. Org 37663 increased the uterus weight in WT and ERβ(-/-) but not in ERα(-/-) mice which indicates that the Org 37663 induced increase in uterus weight is mediated via ERα. As expected, dexamethasone and the ERβ agonist ERB-041 had no effect on the uterus weight. In addition, Org 37663 was found to suppress the inflammatory response in the TT-DTH in WT, ERβ(-/-) but not in ERα(-/-) mice, suggesting that suppression of inflammation is mediated via ERα. Treatment with Org 37663 dose-dependently suppressed the clinical signs in CIA. This was associated with reduced inflammatory infiltrates, and with a reduction in cartilage and bone destruction in the joint. In addition, treatment with Org 37663 decreased the levels of IL-1, IL-6, IL-12p40, KC and Rantes in joints of mice. Reduced cartilage destruction was confirmed by decreased serum levels of cartilage COMP. Dynamics of bone metabolism were not influenced by EE. Org 37663 both decreased osteocalcin and CTX-I. Interestingly, treatment with EE equally suppressed arthritis, whereas ERB-041 (ERβ selective) failed to suppress arthritis symptoms.Conclusion: These data indicate that, in mice, the inflammatory response in both the TT-DTH and in the collagen-induced arthritis model is mediated via ERα. These preclinical data warrant the investigation of the ERα agonist Org 37633 in the treatment of chronic inflammatory conditions such as rheumatoid arthritis.Citation: Ann Rheum Dis, volume 65, supplement II, year 2006, page 128Session: RA-etiology, pathogenesis and animal models