title: Bosentan, an endothelin receptor antagonist, ameliorates collagen-induced arthritis: the role of TNF-α in the induction of endothelin system genes.
abstract: OBJECTIVE
  Endothelins (ETs) are involved in several inflammatory events. The present study investigated the efficacy of bosentan, a dual ETA/ETB receptor antagonist, in collagen-induced arthritis (CIA) in mice.
  
  
  METHODS
  CIA was induced in DBA/1J mice. Arthritic mice were treated with bosentan (100 mg/kg) once a day, starting from the day when arthritis was clinically detectable.
  
  
  METHODS
  CIA progression was assessed by measurements of visual clinical score, paw swelling and hypernociception. Histological changes, neutrophil infiltration and pro-inflammatory cytokines were evaluated in the joints. Gene expression in the lymph nodes of arthritic mice was evaluated by microarray technology. PreproET-1 mRNA expression in the lymph nodes of mice and in peripheral blood mononuclear cells (PBMCs) was evaluated by real-time PCR. The differences were evaluated by one-way ANOVA or Student's t test.
  
  
  RESULTS
  Oral treatment with bosentan markedly ameliorated the clinical aspects of CIA (visual clinical score, paw swelling and hyperalgesia). Bosentan treatment also reduced joint damage, leukocyte infiltration and pro-inflammatory cytokine levels (IL-1β, TNFα and IL-17) in the joint tissues. Changes in gene expression in the lymph nodes of arthritic mice returned to the levels of the control mice after bosentan treatment. PreproET mRNA expression increased in PBMCs from rheumatoid arthritis (RA) patients but returned to basal level in PBMCs from patients under anti-TNF therapy. In-vitro treatment of PBMCs with TNFα upregulated ET system genes.
  
  
  CONCLUSIONS
  These findings indicate that ET receptor antagonists, such as bosentan, might be useful in controlling RA. Moreover, it seems that ET mediation of arthritis is triggered by TNFα.
authors.affiliation: Post Graduation Program in Basic and Applied Immunology, School of Medicine of Ribeirão Preto, University of São Paulo, Avenue Bandeirantes, 3900, Ribeirão Preto, São Paulo 14049-900, Brazil.
authors.forename: Paula B
authors.initials: PB
authors.lastname: Donate
authors.forename: Thiago M
authors.initials: TM
authors.lastname: Cunha
authors.forename: Waldiceu A
authors.initials: WA
authors.lastname: Verri
authors.forename: Cristina M
authors.initials: CM
authors.lastname: Junta
authors.forename: Flavia O
authors.initials: FO
authors.lastname: Lima
authors.forename: Silvio M
authors.initials: SM
authors.lastname: Vieira
authors.forename: Rafael S
authors.initials: RS
authors.lastname: Peres
authors.forename: Karina F
authors.initials: KF
authors.lastname: Bombonato-Prado
authors.forename: Paulo
authors.initials: P
authors.lastname: Louzada
authors.forename: Sergio H
authors.initials: SH
authors.lastname: Ferreira
authors.forename: Eduardo A
authors.initials: EA
authors.lastname: Donadi
authors.forename: Geraldo A S
authors.initials: GA
authors.lastname: Passos
authors.forename: Fernando Q
authors.initials: FQ
authors.lastname: Cunha
mesh_terms: D000328:Adult; D000818:Animals; D018501:Antirheumatic Agents / Q000627:therapeutic use; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000378:metabolism; D000077300:Bosentan; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism*; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000235:genetics / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007963:Leukocytes, Mononuclear; D008198:Lymph Nodes / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008727:Methotrexate / Q000627:therapeutic use; D051379:Mice; D008811:Mice, Inbred DBA; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000378:metabolism; D013449:Sulfonamides / Q000627:therapeutic use*
chemical_list: D018501:Antirheumatic Agents; D016207:Cytokines; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D012333:RNA, Messenger; D013449:Sulfonamides; D000077300:Bosentan; D008727:Methotrexate