HMBG-1 Plays a role in the Pathogenesis of Arthritis
Nuclear high mobility group box chromosomal protein 1 (HMGB-1) is a ubiquitous DNA binding protein involved in multiple functions, including DNA transcription, recombination, and cell replication and migration. However, extracellular HMBG-1 was recently shown to act as a cytokine mediating delayed endotoxin lethality and acute lung injury in mice. Extracellular HMGB-1 has also been detected in the synovial fluid of rheumatoid arthritis patients. Pullerits et al (Arthritis Rheum 48:1693, 2003) now examine the potential role of HMBG-1 in the pathogenesis of arthritis in mice.
Methods: Various mouse strains were injected with 1 mg or 5 mg of recombinant HMGB-1 (rHMGB-1) to assess its ability to induce arthritis. Histopathologic and immunohistochemical examination was performed on the knee joints of sacrificed mice 4, 7, and 28 days after injection. Additionally, the role of different leukocyte populations was assessed using in vivo cell depletion procedures.
Results: Although none of the injected mice showed clinical signs of arthritis, NMRI mice injected with 5 mg of HMGB-1 developed arthritis in 92% of cases by day 4 and 79% of cases by day 7 compared with 9% and 6% of mice, respectively, injected with control buffer. HMGB-1 was found to be arthritogenic in the healthy mouse strains NMRI, C57BL/6, and CB17. When measured 7 days after injection of 5 mg rHMGB-1, joint inflammation occurred in 80% of CB17I mice, 79% of NMRi mice, and 40% of C57BL/6 mice.
Using morphologic evaluation of injected joints to characterize arthritis severity, the highest severity scores were found on days 4 and 7, significantly decreasing by day 28. The synovial membrane lining was noticeably thickened. Inflammatory cells were found throughout the synovial tissue and around blood vessels, largely made up of granulocytes, monocytes, and macrophages. Few CD4+ lymphocytes and no CD8+ cells were detected. When CB17 mice were simultaneously depleted of monocytes and neutrophils, a lower frequency of arthritis (37%), and lower severity of arthritis, were observed.
rHMGB-1 did not to induce arthritis in IL-1 knockout mice. IL-1 synthesis is mediated by the activation of NF-kB. Incubation of spleen cells for 2 hours with varying concentrations of rHMGB-1 resulted in a dose-dependent activation of NF-kB evidenced by electrophoretic mobility shift assay (EMSA).
Conclusion: HMGB-1 appears to play an important role in the pathogenesis of arthritis through the activation of macrophages and monocytes. Its proinflammatory action is mediated, at least in part, by NF-kB activated IL-1 induction. HMGB-1 is a potential target for future therapy.
Editorial Comments: This is an interesting chromatin-associated protein that also has potent proinflammatory effects when present extracellularly. It can be released from monocytes/macrophages by IL-1 and TNF and therefore appears to be a central mediator of the innate immune response.
The fact that treatment of mice with HMGB-1 in this study elicited microscopic, but not macroscopic, evidence of an inflammatory arthritis calls its significance and relevance somewhat into question. Nevertheless, because of its intimate relationship to the innate immune response, which plays a major role in the pathogenesis of rheumatoid arthritis, it deserves further study as a potential therapeutic target in inflammatory arthritis.
