title: Therapeutic efficacy of intra-articular adrenomedullin injection in antigen-induced arthritis in rabbits.
abstract: BACKGROUND
  Adrenomedullin is a potent vasodilatory and hypotensive peptide as well as an endogenous immunomodulatory factor with predominantly anti-inflammatory effects. The purpose of the present study was to evaluate the therapeutic effects of adrenomedullin in rabbits with antigen-induced arthritis, an experimental model of rheumatoid arthritis.
  
  
  METHODS
  Following the induction of arthritis in both knee joints by ovalbumin injection into the joint spaces of pre-immunized rabbits, increasing daily doses of adrenomedullin were injected into the knee joint spaces or saline was injected into the contralateral knee joint spaces as the control. For time-course experiments, adrenomedullin and saline were injected into the knee joint spaces daily for 7 days and 20 days. The degree of joint swelling and the histological change in the knee joints injected with adrenomedullin were compared with the control knee joints. Histological evaluation of the infrapatellar fat pads and synovial tissue was performed. TNFalpha, IL-6, vascular endothelial growth factor and transforming growth factor-beta mRNA levels in the synovial tissue were measured using real-time quantitative PCR.
  
  
  RESULTS
  Daily injections of adrenomedullin into the knee joint spaces of rabbits with antigen-induced arthritis decreased joint swelling. Histological examination revealed that adrenomedullin reduced edematous changes and the infiltration of inflammatory cells in the synovial tissues. Analysis of mRNA levels showed that adrenomedullin significantly reduced TNFalpha mRNA expression by 21% to 49% in a dose-dependent manner, and dose-dependently increased IL-6 mRNA expression by 45% to 121%.
  
  
  CONCLUSIONS
  These results suggest that daily injections of adrenomedullin into the knee joint spaces of rabbits with antigen-induced arthritis ameliorated the inflammatory response in arthritic joints. Adrenomedullin may thus be useful as a treatment for rheumatoid arthritis; however, the effect of adrenomedullin on IL-6 production in the synovial tissue may be an undesirable adverse effect in rheumatoid arthritis therapy.
authors.affiliation: Department of Medicine of Sensory and Motor Organs, Division of Orthopedic Surgery, Faculty of Medicine, University of Miyazaki, Kiyotake, Miyazaki, Japan. okuratoshi@med.miyazaki-u.ac.jp
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Okura
authors.forename: Kousuke
authors.initials: K
authors.lastname: Marutsuka
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Hamada
authors.forename: Tomohisa
authors.initials: T
authors.lastname: Sekimoto
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Fukushima
authors.forename: Yujiro
authors.initials: Y
authors.lastname: Asada
authors.forename: Kazuo
authors.initials: K
authors.lastname: Kitamura
authors.forename: Etsuo
authors.initials: E
authors.lastname: Chosa
mesh_terms: D053607:Adrenomedullin / Q000008:administration & dosage*; D000818:Animals; D000941:Antigens / Q000633:toxicity; D001169:Arthritis, Experimental / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D005260:Female; D007270:Injections, Intra-Articular; D010047:Ovalbumin / Q000633:toxicity*; D011817:Rabbits
chemical_list: D000941:Antigens; D053607:Adrenomedullin; D010047:Ovalbumin