Suppression of the inflammatory response in experimental arthritis is mediated via estrogen receptor α but not estrogen receptor β

Abstract

IntroductionThe immune modulatory role of estrogens in inflammation is complex. Both pro- and anti-inflammatory effects of estrogens have been described. Estrogens bind both estrogen receptor (ER)α and β. The contribution of ERα and ERβ to ER-mediated immune modulation was studied in delayed type hypersensitivity (DTH) and in experimental arthritisMethodsER-mediated suppression of rat adjuvant arthritis (AA) was studied using ethinyl-estradiol (EE) and a selective ERβ agonist (ERB-79). Arthritis was followed for 2 weeks. Next, effects of ER agonists (ethinyl-estradiol, an ERα selective agonist (ERA-63) and a selective ERβ agonist (ERB-79) on the development of a tetanus toxoid (TT)-specific delayed type hypersensitivity response in wild type (WT) and in ERα - or ERβ-deficient mice were investigated. Finally, EE and ERA-63 were tested for their immune modulating potential in established collagen induced arthritis in DBA/1J mice. Arthritis was followed for three weeks. Joint pathology was examined by histology and radiology. Local synovial cytokine production was analyzed using Luminex technology. Sera were assessed for COMP as a biomarker of cartilage destruction.ResultsEE was found to suppress clinical signs and symptoms in rat AA. The selective ERβ agonist ERB-79 had no effect on arthritis symptoms in this model. In the TT-specific DTH model, EE and the selective ERα agonist ERA-63 suppressed the TT-specific swelling response in WT and ERβKO mice but not in ERαKO mice. As seen in the AA model, the selective ERβ agonist ERB-79 did not suppress inflammation. Treatment with EE or ERA-63 suppressed clinical signs in collagen induced arthritis (CIA) in WT mice. This was associated with reduced inflammatory infiltrates and decreased levels of proinflammatory cytokines in CIA joints.ConclusionsERα, but not ERβ, is key in ER-mediated suppression of experimental arthritis. It remains to be investigated how these findings translate to human autoimmune disease.

The role of total and cartilage-specific estrogen receptor alpha expression for the ameliorating effect of estrogen treatment on arthritis

“…ERβ activation has also been implicated to play a role in the amelioration of arthritis in males [32,33]. However, we and others have shown, in both female and male rodents, that ERα, and not ERβ, activation ameliorates arthritis [5,31]. Furthermore, in the present study, E2 treatment was not able to ameliorate arthritis in ERα inactivated mice despite the presence of ERβ, demonstrating that ERα is the main receptor mediating the protective effects of estrogen on arthritis.…”

Pathophysiology of rheumatoid arthritis

“…Oestrogens are known to be anti-inflammatory and, in a rat model of adjuvant arthritis, ethinyl-estradiol (via estrogen receptor-a) suppressed clinical signs and symptoms [52]. Polymorphisms in the glucocorticoid receptor gene also affect RA susceptibility and, as well as effectively suppressing inflammation, glucocorticoids may be important in disease pathogenesis [53].…”

Glucose Kinetics in the Collagen-Induced Arthritis Model: An All-in-One Model to Assess Both Efficacy and Metabolic Side Effects of Glucocorticoids

“…The dose of 12 mg/kg/day for ORG 37663 was selected because this dose is comparable to a dose of 10 mg/kg/day prednisolone regarding efficacy [6]. In total, 36 arthritic mice (12 per treatment group) and 36 non-arthritic control mice, like described above, were included in this consecutive experiment.…”