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

Introduction: Estrogen (E2) delays onset and decreases severity of experimental arthritis. The aim of this study was to investigate the importance of total estrogen receptor alpha (ERa) expression and cartilage-specific ERa expression in genetically modified mice for the ameliorating effect of estrogen treatment in experimental arthritis. Methods: Mice with total (total ER alpha(-/-)) or cartilage-specific (Col2 alpha 1-ER alpha(-/-)) inactivation of ERa and wild-type (WT) littermates were ovariectomized, treated with E2 or placebo, and induced with antigen-induced arthritis (AIA). At termination, knees were collected for histology, synovial and splenic cells were investigated by using flow cytometry, and splenic cells were subjected to a T-cell proliferation assay. Results: E2 decreased synovitis and joint destruction in WT mice. Amelioration of arthritis was associated with decreased frequencies of inflammatory cells in synovial tissue and decreased splenic T-cell proliferation. E2 did not affect synovitis or joint destruction in total ER alpha(-/-)mice. In Col2 alpha 1-ER alpha(-/-)mice, E2 protected against joint destruction to a similar extent as in WT mice. In contrast, E2 did not significantly ameliorate synovitis in Col2 alpha 1-ER alpha(-/-) mice. Conclusions: Treatment with E2 ameliorates both synovitis and joint destruction in ovariectomized mice with AIA via ERa. This decreased severity in arthritis is associated with decreased synovial inflammatory cell frequencies and reduced splenic T-cell proliferation. ERa expression in cartilage is not required for estrogenic amelioration of joint destruction. However, our data indicate that ERa expression in cartilage is involved in estrogenic effects on synovitis, suggesting different mechanisms for the amelioration of joint destruction and synovitis by E2.