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


CONCLUSIONS
These findings indicate that tissue hypoxia and its resultant extracellular HMGB-1 might play an important role in the development of arthritis.
Hamada
Takashi
T
Kagoshima University, Kagoshima, Japan.
Torikai
Motofumi
M
Kuwazuru
Ai
A
Tanaka
Motoyuki
M
Horai
Naoto
N
Fukuda
Takeshi
T
Yamada
Shingo
S
Nagayama
Shinichi
S
Hashiguchi
Kanehisa
K
Sunahara
Nobuhiko
N
Fukuzaki
Koichiro
K
Nagata
Ryoichi
R
Komiya
Setsuro
S
Maruyama
Ikuro
I
Fukuda
Takeo
T
Abeyama
Kazuhiro
K