Conclusion. These results demonstrate that FR-␤ expression is selectively elevated in RA synovial macrophages and suggest that MTX is transported through FR-␤ in RA synovial macrophages. The findings suggest that folate antagonists with higher affinity for FR-␤ would be useful in the treatment of RA.

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 ␣, 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 cellbased 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.High mobility group box chromosomal protein 1 (HMGB-1) is a nuclear architectural protein that is released from necrotic cells (1) and/or secreted from activated macrophages (2,3). It has been identified as a mediator of endotoxin-induced lethality (2,4) and a causative factor in arthritis (3,5-7), acting, at least in part, as a proinflammatory cytokine (1-11). Engagement of the receptor for advanced glycation end products (RAGE) by extracellular HMGB-1 triggers activation of proinflammatory signaling pathways (10,11), such as those resulting in elaboration of reactive oxygen inter-

The distribution and M1/M2 expression profiles of FR-β+ synovial macrophages were different between OA and RA synovial tissues. Thus, the findings underscore that the M1/M2 paradigm using surface markers FR-β and CD163 is an oversimplification of macrophage subsets. Functional FR-β present on OA synovial macrophages provides a potential tool for the diagnosis and treatment of OA.

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The clinical results for rheumatoid arthritis patients with myelopathy treated without surgery are extremely poor. Surgical treatment is recommended for rheumatoid arthritis patients with myelopathy.