title: Erythropoietin reduces the degree of arthritis caused by type II collagen in the mouse.
abstract: OBJECTIVE
  Erythropoietin (EPO) is a potent stimulator of erythroid progenitor cells, and its expression is enhanced by hypoxia. The aim of this study was to investigate the effect of EPO on collagen-induced arthritis (CIA) in the mouse.
  
  
  METHODS
  CIA was induced by intradermal injection of bovine type II collagen (CII) and Freund's complete adjuvant. Starting on day 25, some of the mice with CIA received daily subcutaneous injections of EPO (1,000 units/kg). Two other groups of mice received sham treatment alone or sham treatment followed by EPO treatment, respectively. Arthritis was assessed clinically, radiologically, and histologically. Cytokine and chemokine levels were measured, and neutrophil infiltration into inflamed joints was quantitated. Immunohistochemistry studies were performed to measure protein nitrosylation. Chondrocyte apoptosis was assessed by TUNEL assay.
  
  
  RESULTS
  Macroscopic clinical evidence of CIA first appeared as periarticular erythema and edema in the hind paws. The incidence of CIA was 100% by day 27 in the CII-challenged mice, and the severity of CIA progressed over a 35-day period, with radiographic evaluation revealing focal resorption of bone. Histopathologic features of CIA included erosion of the cartilage at the joint margins. Treatment with EPO starting at the onset of arthritis (day 25) ameliorated the clinical signs on days 26-35 and improved histologic status in the joints and paws. The degree of oxidative and nitrosative damage was significantly reduced in EPO-treated mice as indicated by decreased nitrotyrosine formation and poly(ADP-ribose) polymerase activation. Plasma levels of the proinflammatory cytokine tumor necrosis factor alpha were also significantly reduced by EPO treatment. In addition, EPO reduced the levels of apoptosis in chondrocytes in articular cartilage, as indicated by decreased TUNEL staining.
  
  
  CONCLUSIONS
  These findings demonstrate that EPO exerts an antiinflammatory effect during chronic inflammation and is able to ameliorate the tissue damage associated with CIA.
authors.affiliation: University of Messina, Messina, Italy. salvator@unime.it <salvator@unime.it>
authors.forename: Salvatore
authors.initials: S
authors.lastname: Cuzzocrea
authors.forename: Emanuela
authors.initials: E
authors.lastname: Mazzon
authors.forename: Rosanna
authors.initials: R
authors.lastname: di Paola
authors.forename: Tiziana
authors.initials: T
authors.lastname: Genovese
authors.forename: Nimesh S A
authors.initials: NS
authors.lastname: Patel
authors.forename: Domenico
authors.initials: D
authors.lastname: Britti
authors.forename: Massimo
authors.initials: M
authors.lastname: de Majo
authors.forename: Achille P
authors.initials: AP
authors.lastname: Caputi
authors.forename: Christoph
authors.initials: C
authors.lastname: Thiemermann
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000276:immunology; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002358:Cartilage, Articular; D018925:Chemokines / Q000378:metabolism; D019902:Chondrocytes / Q000502:physiology; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004921:Erythropoietin / Q000008:administration & dosage / Q000494:pharmacology*; D006397:Hematinics / Q000008:administration & dosage / Q000494:pharmacology*; D007279:Injections, Subcutaneous; D051379:Mice; D008811:Mice, Inbred DBA; D020556:Neutrophil Infiltration / Q000276:immunology; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000378:metabolism
chemical_list: D018925:Chemokines; D016207:Cytokines; D006397:Hematinics; D004921:Erythropoietin; C002744:3-nitrotyrosine; D014443:Tyrosine; D011065:Poly(ADP-ribose) Polymerases