title: The role of total and cartilage-specific estrogen receptor alpha expression for the ameliorating effect of estrogen treatment on arthritis.
abstract: BACKGROUND
  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.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Engdahl
authors.forename: Anna E
authors.initials: AE
authors.lastname: Börjesson
authors.forename: Huamei F
authors.initials: HF
authors.lastname: Forsman
authors.forename: Annica
authors.initials: A
authors.lastname: Andersson
authors.forename: Alexandra
authors.initials: A
authors.lastname: Stubelius
authors.forename: Andree
authors.initials: A
authors.lastname: Krust
authors.forename: Pierre
authors.initials: P
authors.lastname: Chambon
authors.forename: Ulrika
authors.initials: U
authors.lastname: Islander
authors.forename: Claes
authors.initials: C
authors.lastname: Ohlsson
authors.forename: Hans
authors.initials: H
authors.lastname: Carlsten
authors.forename: Marie K
authors.initials: MK
authors.lastname: Lagerquist
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000378:metabolism / Q000473:pathology*; D001172:Arthritis, Rheumatoid / Q000378:metabolism / Q000473:pathology*; D002356:Cartilage / Q000187:drug effects / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D004958:Estradiol / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000096:biosynthesis*; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D005434:Flow Cytometry; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010052:Ovariectomy; D060888:Real-Time Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000187:drug effects
chemical_list: D047628:Estrogen Receptor alpha; D004967:Estrogens; D004958:Estradiol