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Open Access Highly Accessed Research article

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

Cecilia Engdahl12*, Anna E Börjesson2, Huamei F Forsman1, Annica Andersson1, Alexandra Stubelius1, Andree Krust3, Pierre Chambon3, Ulrika Islander1, Claes Ohlsson2, Hans Carlsten1 and Marie K Lagerquist12

Author Affiliations

1 Department of Rheumatology and Inflammation Research, Centre for Bone and Arthritis Research, Institute of Medicine, University of Gothenburg, Box 480, 405 30 Gothenburg, Sweden

2 Department of Internal Medicine and Clinical Nutrition, Centre for Bone and Arthritis Research, Institute of Medicine, University of Gothenburg, Vita Stråket 11, 413 45 Gothenburg, Sweden

3 Department of Functional Genomics, IGBMC, Collège de France, B.P. 10142, 674 04 Illkirch, France

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Arthritis Research & Therapy 2014, 16:R150  doi:10.1186/ar4612

Published: 15 July 2014

Abstract

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 (ERα) expression and cartilage-specific ERα expression in genetically modified mice for the ameliorating effect of estrogen treatment in experimental arthritis.

Methods

Mice 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.

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 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.

Conclusions

Treatment 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.