title: Successful treatment of collagen-induced arthritis in mice and rats by targeting extracellular high mobility group box chromosomal protein 1 activity.
abstract: OBJECTIVE
  Extracellular high mobility group box chromosomal protein 1 (HMGB-1) is a recently identified, endogenous, potent tumor necrosis factor- and interleukin-1 (IL-1)-inducing protein detectable in inflamed synovia in both human and experimental disease. In the present study, we examined clinical effects in collagen-induced arthritis (CIA) using therapeutic administration of neutralizing HMGB-1 antibodies or truncated HMGB-1-derived A-box protein, a specific, competitive antagonist of HMGB-1.
  
  
  METHODS
  CIA was induced in DBA/1j mice or dark agouti rats, and animals were examined daily for signs of arthritis. Treatment with polyclonal anti-HMGB-1 antibodies or the A-box protein was initiated at the onset of disease and was administered intraperitoneally twice daily for 7 days. Animals were killed 8 days after initiation of therapy, and immunohistochemical analysis of synovial tissue specimens was performed.
  
  
  RESULTS
  Systemic administration of anti-HMGB-1 antibodies or A-box protein significantly reduced the mean arthritis score, the disease-induced weight loss, and the histologic severity of arthritis. Beneficial effects were observed in both mice and rats. Immunohistochemical analysis revealed pronounced synovial IL-1beta expression and articular cartilage destruction in vehicle-treated mice. Both these features were significantly less manifested in animals treated with anti-HMGB-1 antibodies or A-box protein.
  
  
  CONCLUSIONS
  Counteracting extracellular HMGB-1 with either neutralizing antibodies or a specific HMGB-1 antagonist may offer a new method for the successful treatment of arthritis. Inflammation and tissue destruction were suppressed in CIA after HMGB-1 blockade.
authors.affiliation: Rheumatology Research Unit, CMM L8:04, Karolinska Hospital, Stockholm 171 76, Sweden. Riikka.Kokkola@cmm.ki.se
authors.forename: R
authors.initials: R
authors.lastname: Kokkola
authors.forename: J
authors.initials: J
authors.lastname: Li
authors.forename: E
authors.initials: E
authors.lastname: Sundberg
authors.forename: A-C
authors.initials: AC
authors.lastname: Aveberger
authors.forename: K
authors.initials: K
authors.lastname: Palmblad
authors.forename: H
authors.initials: H
authors.lastname: Yang
authors.forename: K J
authors.initials: KJ
authors.lastname: Tracey
authors.forename: U
authors.initials: U
authors.lastname: Andersson
authors.forename: H Erlandsson
authors.initials: HE
authors.lastname: Harris
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000473:pathology; D002358:Cartilage, Articular / Q000473:pathology; D005110:Extracellular Space; D005260:Female; D024243:HMGB1 Protein / Q000276:immunology / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D051381:Rats; D011919:Rats, Inbred Strains; D013583:Synovial Membrane / Q000473:pathology
chemical_list: D000906:Antibodies; D024243:HMGB1 Protein