Abstract
High mobility group box chromosomal protein 1 (HMGB1) is a DNA-binding nuclear protein that can be released from dying cells and activated myeloid cells. Extracellularly, HMGB1 promotes inflammation. Experimental studies demonstrate HMGB1 to be a pathogenic factor in many inflammatory conditions including arthritis. HMGB1-blocking therapies in arthritis models alleviate disease and confer significant protection against cartilage and bone destruction. So far, the most successful HMGB1-targeted therapies have been demonstrated with HMGB1-specific polyclonal antibodies and with recombinant A box protein, a fragment of HMGB1. The present study is the first to evaluate the potential of a monoclonal anti-HMGB1 antibody (2G7, mouse IgG2b) to ameliorate arthritis. Effects of repeated injections of this antibody have now been studied in two conceptually different models of arthritis: collagen type II-induced arthritis (CIA) in DBA/1 mice and in a spontaneous arthritis disease in mice with combined deficiencies for genes encoding for the enzyme DNase type II and interferon type I receptors. These mice are unable to degrade phagocytozed DNA in macrophages and develop chronic, destructive polyarthritis. Therapeutic intervention in CIA and prophylactic administration of anti-HMGB1 monoclonal antibody (mAb) in the spontaneous arthritis model significantly ameliorated the clinical courses. Anti-HMGB1 mAb therapy also partially prevented joint destruction, as demonstrated by histological examination. The beneficial antiarthritic effects by the anti-HMGB1 mAb in two diverse models of arthritis represent additional proof-of-concept, indicating that HMGB1 may be a valid target molecule to consider for development of future clinical therapy.
Highlights
Chronic arthritides are inflammatory diseases associated with decreased quality of life and disability due to fatigue, pain and articular tissue destruction
Increased systemic High mobility group box chromosomal protein 1 (HMGB1) levels have previously been documented in sera of DNase II –/– × interferon type I receptor (IFN-IR)–/– mice, occurring even before onset of clinical disease and intraarticular HMGB1 release [19]
Prophylactic administration of the anti-HMGB1 monoclonal antibody (mAb) every second day for 5 wks to DNase II –/– × IFNIR–/– animals significantly reduced the clinical severity, as revealed by lower clinical arthritis scores compared with controls (P = 0.02) (Figure 1)
Summary
Chronic arthritides are inflammatory diseases associated with decreased quality of life and disability due to fatigue, pain and articular tissue destruction. Despite the clinical success of biologics in the treatment of chronic arthritis, there are still many patients with unmet medical needs. High mobility group box chromosomal protein 1 (HMGB1) is a nonhistone DNA-binding nuclear protein that displays both intracellular and extracellular activities. HMGB1 exerts structural and transcriptional activities [1,2,3]. Extracellular HMGB1 is a potent endogenous “danger signal” for the initiation of innate immunity. The translocation of HMGB1 from the inside to the outside of the cell is a critical event in host defense and inflammation and can occur via two separate mechanisms. HMGB1 may be actively released by inflammatory cells after stimulation with exogenous pathogen-derived molecules or endogenous inflammatory mediators as well as in response to ischemia [4,5,6,7]
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