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

Abstract

IntroductionEstrogen (E2) delays onset and decreases severity of experimental arthritis. The aim of this study was to investigate the importance of total estrogen receptor alpha (ERα) expression and cartilage-specific ERα expression in genetically modified mice for the ameliorating effect of estrogen treatment in experimental arthritis.MethodsMice with total (total ERα-/-) or cartilage-specific (Col2α1-ERα-/-) inactivation of ERα 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.ResultsE2 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 ERα-/- mice. In Col2α1-ERα-/- mice, E2 protected against joint destruction to a similar extent as in WT mice. In contrast, E2 did not significantly ameliorate synovitis in Col2α1-ERα-/- mice.ConclusionsTreatment with E2 ameliorates both synovitis and joint destruction in ovariectomized mice with AIA via ERα. This decreased severity in arthritis is associated with decreased synovial inflammatory cell frequencies and reduced splenic T-cell proliferation. ERα expression in cartilage is not required for estrogenic amelioration of joint destruction. However, our data indicate that ERα expression in cartilage is involved in estrogenic effects on synovitis, suggesting different mechanisms for the amelioration of joint destruction and synovitis by E2.

Selective estrogen receptor modulators in T cell development and T cell dependent inflammation

“…It has repeatedly been shown that treatment with E2 improves disease development in experimental models of arthritis (Jansson and Holmdahl, 1989;Nandakumar et al, 2003;Engdahl et al, 2014) shown that the second generation SERM ral inhibits experimental postmenopausal arthritis (Jochems et al, 2007). Interestingly, preliminary data from our lab show that also las and bza have beneficial effects on disease development and associated bone loss in postmenopausal collagen-induced arthritis (Andersson et al, submitted).…”

IL-17-producing γδT cells are regulated by estrogen during development of experimental arthritis

“…We previously reported that E2, acting via ERα, inhibits synovitis and erosions on cartilage and bone in the monoarthritic AIA model [24]. Herein, we used the AIA model to confirm E2-mediated effects on IL-17 + γδT cells in arthritis, as well as determining the role of ERα in these effects.…”

“…Experiment was terminated day 14. Arthritis data and other details regarding AIA is described elsewhere [24].…”

“…Furthermore, women with RA often experience improved joint disease symptoms during pregnancy (afflicted with high levels of estrogens), and estradiol-containing hormone replacement therapy (HRT) given to postmenopausal RA patients improved joint disease activity in some studies but not in others [20][21][22][23]. Nevertheless, treatment with estrogens dramatically inhibits arthritis in various animal models of RA; antigen-induced arthritis (AIA), collagen antibody-induced arthritis (CAIA) and CIA [24][25][26][27]. The mechanisms underlying estrogenmediated inhibition of arthritis are still not fully elucidated; however, we recently reported that E2 regulates Th17 cell localization during development of CIA.…”

The interconnected role of chemokines and estrogen in bone metabolism

“…In EAE, estrogen down-regulates IL-17 production and it inhibits Th17 differentiation through estrogen receptor α (ERα) in T cells (102,(104)(105)(106)). An estrogen deficiency increases the amount of Th17 cells in bone marrow and IL-17 levels.…”