Successful treatment of collagen‐induced arthritis in mice and rats by targeting extracellular high mobility group box chromosomal protein 1 activity

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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‐1β 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. Conclusion 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.

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