Extracellular high mobility group box chromosomal protein 1 is a coupling factor for hypoxia and inflammation in arthritis

Takashi Hamada, Motofumi Torikai, Ai Kuwazuru, Motoyuki Tanaka, Naoto Horai, Takeshi Fukuda, Shingo Yamada, Shinichi Nagayama, Kanehisa Hashiguchi, Nobuhiko Sunahara, Koichiro Fukuzaki, Ryoichi Nagata, Setsuro Komiya, Ikuro Maruyama, Takeo Fukuda, Kazuhiro Abeyama

Research output: Contribution to journalArticlepeer-review

106 Citations (Scopus)


Objective. Tissue hypoxia is closely associated with arthritis pathogenesis, and extracellular high mobility group box chromosomal protein 1 (HMGB-1) released from injured cells also has a role in arthritis development. This study was thus undertaken to investigate the hypothesis that extracellular HMGB-1 may be a coupling factor between hypoxia and inflammation in arthritis. Methods. Concentrations of tumor necrosis factor a, interleukin-6, vascular endothelial growth factor, lactic acid, lactate dehydrogenase, and HMGB-1 were measured in synovial fluid (SF) samples from patients with inflammatory arthropathy (rheumatoid arthritis and pseudogout) and patients with noninflammatory arthropathy (osteoarthritis). The localization of tissue hypoxia and HMGB-1 was also examined in animal models of collagen-induced arthritis (CIA). In cell-based experiments, the effects of hypoxia on HMGB-1 release and its associated cellular events (i.e., protein distribution and cell viability) were studied. Results. In SF samples from patients with HMGB-1-associated inflammatory arthropathy (i.e., samples with HMGB-1 levels >2 SD above the mean level in samples from patients with noninflammatory arthropathy), concentrations of HMGB-1 were significantly correlated with those of lactic acid, a marker of tissue hypoxia. In CIA models in which the pathologic phenotype could be attenuated by HMGB-1 neutralization, colocalization of HMGB-1 with tissue hypoxia in arthritis lesions was also observed. In cell-based experiments, hypoxia induced significantly increased levels of extracellular HMGB-1 by the cellular processes of secretion and/or apoptosis-associated release, which was much more prominent than the protein release in necrotic cell injury potentiated by oxidative stress. Conclusion. These findings indicate that tissue hypoxia and its resultant extracellular HMGB-1 might play an important role in the development of arthritis.

Original languageEnglish
Pages (from-to)2675-2685
Number of pages11
JournalArthritis and rheumatism
Issue number9
Publication statusPublished - Sept 2008
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Rheumatology
  • Immunology
  • Pharmacology (medical)


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