Successful treatment of collagen-induced arthritis in mice and rats by targeting extracellular high mobility group box chromosomal protein 1 activity.
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.
Kokkola
R
R
Rheumatology Research Unit, CMM L8:04, Karolinska Hospital, Stockholm 171 76, Sweden. Riikka.Kokkola@cmm.ki.se
Li
J
J
Sundberg
E
E
Aveberger
A-C
AC
Palmblad
K
K
Yang
H
H
Tracey
K J
KJ
Andersson
U
U
Harris
H Erlandsson
HE
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
D000906:Antibodies; D024243:HMGB1 Protein