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. 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.
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. 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.
Authors: Konstantin Stark; Vanessa Philippi; Sven Stockhausen; Johanna Busse; Antonella Antonelli; Meike Miller; Irene Schubert; Parandis Hoseinpour; Sue Chandraratne; Marie-Luise von Brühl; Florian Gaertner; Michael Lorenz; Alessandra Agresti; Raffaele Coletti; Daniel J Antoine; Ralf Heermann; Kirsten Jung; Sven Reese; Iina Laitinen; Markus Schwaiger; Axel Walch; Markus Sperandio; Peter P Nawroth; Christoph Reinhardt; Sven Jäckel; Marco E Bianchi; Steffen Massberg Journal: Blood Date: 2016-08-29 Impact factor: 22.113