Molecular Medicine

, Volume 17, Issue 9–10, pp 1039–1044 | Cite as

Monoclonal Anti-HMGB1 (High Mobility Group Box Chromosomal Protein 1) Antibody Protection in Two Experimental Arthritis Models

  • Hanna Schierbeck
  • Peter Lundbäck
  • Karin Palmblad
  • Lena Klevenvall
  • Helena Erlandsson-Harris
  • Ulf Andersson
  • Lars Ottosson
Research Article


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.



This study was financially supported through the regional agreement on medical training and clinical research between the Stockholm County Council and Karolinska Institutet, the Swedish Medical Research Council, the Swedish Association against Rheumatism, Åke Wiberg’s Foundation, the Freemason Lodge Barnhuset in Stockholm, Kronprinsessan Lovisas Stiftelse and King Gustaf V’s Foundation.


  1. 1.
    Johns EW, Goodwin CHM, Walker JM, Sanders C. (1975) Chromosomal proteins related to histones. Ciba Found. Symp. 28:95–112.Google Scholar
  2. 2.
    Bustin M, Reeves R. (1996) High-mobility-group chromosomal proteins: architectural components that facilitate chromatin function. Prog. Nucleic Acid Res. Mol. Biol. 54:35–100.CrossRefPubMedGoogle Scholar
  3. 3.
    Park JS, et al. (2003) Activation of gene expression in human neutrophils by high mobility group box 1 protein. Am. J. Physiol. Cell. Physiol. 284:C870–9.CrossRefPubMedGoogle Scholar
  4. 4.
    Gardella S, et al. (2002) The nuclear protein HMGB1 is secreted by monocytes via a non-classical, vesicle-mediated secretory pathway. EMBO Rep. 13:995–1001.CrossRefGoogle Scholar
  5. 5.
    Bonaldi T, et al. (2003) Monocytic cells hyper-acetylate chromatin protein HMGB1 to redirect it towards secretion. EMBO J. 22:5551–60.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Dumitriu IE, et al. (2005) Release of high mobility group box 1 by dendritic cells controls T cell activation via the receptor for advanced glycation end products. J. Immunol. 174:7506–15.CrossRefPubMedGoogle Scholar
  7. 7.
    Hamada T, et al. (2008) Extracellular high mobility group box chromosomal protein 1 is a coupling factor for hypoxia and inflammation in arthritis. Arthritis Rheum. 58:2675–85.CrossRefPubMedGoogle Scholar
  8. 8.
    Scaffidi P, Misteli T, Bianchi ME. (2002) Release of chromatin protein HMGB1 by necrotic cells triggers inflammation. Nature. 418:191–5.CrossRefGoogle Scholar
  9. 9.
    Bell CW, Jiang W, Reich CF 3rd, Pisetsky DS. (2006) The extracellular release of HMGB1 during apoptotic cell death. Am. J. Physiol. Cell. Physiol. 291:1318–25.CrossRefGoogle Scholar
  10. 10.
    Yu M, et al. (2006) HMGB1 signals through tolllike receptor (TLR) 4 and TLR2. Shock. 26:174–9.CrossRefGoogle Scholar
  11. 11.
    Yang H, et al. (2010) A critical cysteine is required for HMGB1 binding to Toll-like receptor 4 and activation of macrophage cytokine release. Proc. Natl. Acad. Sci. U. S. A. 107:11942–7.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Hori O, et al. (1995) The receptor for advanced glycation end products (RAGE) is a cellular binding site for amphoterin: mediation of neurite outgrowth and co-expression of RAGE and amphoterin in the developing nervous system. J. Biol. Chem. 270:25752–61.CrossRefGoogle Scholar
  13. 13.
    Kokkola R, et al. (2002) High mobility group box chromosomal protein 1: a novel proinflammatory mediator in synovitis. Arthritis Rheum. 46:2598–603.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Taniguchi N, et al. (2003) High mobility group box chromosomal protein 1 plays a role in the pathogenesis of rheumatoid arthritis as a novel cytokine. Arthritis Rheum. 48:971–81.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    af Klint E, et al. (2005) Intraarticular glucocorticoid treatment reduces inflammation in synovial cell infiltrations more efficiently than in synovial blood vessels. Arthritis Rheum. 52:3880–9.CrossRefPubMedGoogle Scholar
  16. 16.
    Pullerits R, et al. (2003) High mobility group chromosomal protein 1, a DNA-binding cytokine, induces arthritis. Arthritis Rheum. 48:1693–700.CrossRefPubMedGoogle Scholar
  17. 17.
    Kokkola R, et al. (2003) Successful therapy in collagen-induced arthritis in mice and rats targeting extracellular HMGB1 activity. Arthritis Rheum. 48:2052–8.CrossRefPubMedGoogle Scholar
  18. 18.
    Östberg T, et al. (2008) Oxaliplatin retains HMGB1 intranuclearly and ameliorates collagen type II-induced arthritis. Arthritis Res. Ther. 10:R1.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Östberg T, et al. (2010) Protective targeting of high mobility group box chromosomal protein 1 in a spontaneous arthritis model. Arthritis Rheum. 62:2963–72.CrossRefPubMedGoogle Scholar
  20. 20.
    Andersson U, et al. (2000) HMG-1 stimulates proinflammatory cytokine synthesis in human monocytes. J. Exp. Med. 192:565–70.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Parkkinen J, et al. (1993) Amphoterin, the 30-kDa family of HMG1-type polypeptides: enhanced expression in transformed cells, leading edge localization, and interactions with plasminogen activation. J. Biol. Chem. 268:19726–38.PubMedGoogle Scholar
  22. 22.
    Taguchi A, et al. (2000) Blockade of RAGE-amphoterin signalling suppresses tumour growth and metastases. Nature. 405:354–9.CrossRefGoogle Scholar
  23. 23.
    Zhou Z, et al. (2008) HMGB1 regulates RANKL-induced osteoclastogenesis in a manner dependent on RAGE. J. Bone Miner. Res. 23:1084–96.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Yamoah K, et al. (2008) High-mobility group box proteins modulate tumor necrosis factor-alpha expression in osteoclastogenesis via a novel deoxyribonucleic acid sequence. Mol. Endocrinol. 22:1141–53.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Yang J, et al. (2008) HMGB1 is a bone-active cytokine. J. Cell. Physiol. 214:730–9.CrossRefPubMedGoogle Scholar
  26. 26.
    Kawane K, et al. (2006) Chronic polyarthritis caused by mammalian DNA that escapes from degradation in macrophages. Nature. 443:998–1002.CrossRefGoogle Scholar
  27. 27.
    Yoshida H, Okabe Y, Kawane K, Fukuyama H, Nagata S. (2005) Lethal anemia caused by interferon-beta produced in mouse embryos carrying undigested DNA. Nat. Immunol. 6:49–56.CrossRefPubMedGoogle Scholar
  28. 28.
    Andersson U, Tracey KJ. (2011) HMGB1 is a therapeutic target for sterile and infectious inflammation. Annu. Rev. Immunol. 29:139–62.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Qin S, et al. (2006) Role of HMGB1 in apoptosis-mediated sepsis lethality. J. Exp. Med. 203:1637–42.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Gao Q, et al. (2010) TLR4 mediates early graft failure after intraportal islet transplantation. Am. J. Transplant. 10:1588–96.CrossRefPubMedGoogle Scholar
  31. 31.
    Wähämaa H, et al. (2007) HMGB1-secreting capacity of multiple cell lineages revealed by a novel HMGB1 ELISPOT assay. J. Leukoc. Biol. 81:129–36.CrossRefPubMedGoogle Scholar
  32. 32.
    Palmblad K, et al. (2007) Morphological characterization of intra-articular HMGB1 expression during the course of collagen-induced arthritis. Arthritis Res. Ther. 9:R35.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Liu K, et al. (2007) Anti-high mobility group box 1 monoclonal antibody ameliorates brain infarction induced by transient ischemia in rats. FASEB J. 21:3904–16.CrossRefPubMedGoogle Scholar
  34. 34.
    Hegen M, Keith JC Jr, Collins M, Nickerson-Nutter CL. (2008) Utility of animal models for identification of potential therapeutics for rheumatoid arthritis. Ann. Rheum. Dis. 67:1505–15.CrossRefPubMedGoogle Scholar

Copyright information

© The Feinstein Institute for Medical Research 2011

Authors and Affiliations

  • Hanna Schierbeck
    • 1
  • Peter Lundbäck
    • 2
  • Karin Palmblad
    • 1
  • Lena Klevenvall
    • 1
  • Helena Erlandsson-Harris
    • 2
  • Ulf Andersson
    • 1
  • Lars Ottosson
    • 1
  1. 1.Department of Women’s and Children’s Health, Karolinska InstitutetKarolinska University HospitalStockholmSweden
  2. 2.Department of Medicine, Pediatric Rheumatology Research Unit, Karolinska InstitutetKarolinska University HospitalStockholmSweden

Personalised recommendations