Oxaliplatin retains HMGB1 intranuclearly and ameliorates collagen type II-induced arthritis.
BACKGROUND
High mobility group box chromosomal protein 1 (HMGB1) is a nuclear protein that acts as a pro-inflammatory mediator following extracellular release. The protein is aberrantly expressed extracellularly in the settings of clinical and experimental synovitis. Therapy based on HMGB1 antagonists has shown encouraging results in experimental arthritis and warrants further scientific exploration using independent methods. In the present study we asked whether nuclear sequestration of HMGB1 preventing HMGB1 release would be beneficial for synovitis treatment.


METHODS
Oxaliplatin-based therapy was evaluated in collagen type II-induced arthritis in DBA/1 mice by clinical scoring and immunostaining of articular tissue. Oxaliplatin is an antineoplastic platinum-based compound that generates DNA adducts which tightly bind HMGB1. Secretion and intracellular location of HMGB1 were assessed by a novel HMGB1-specific ELISPOT assay and immunofluorescent staining.


RESULTS
Intraperitoneal injections of oxaliplatin in early collagen type II-induced arthritis trapped HMGB1 with a distinct biphasic response pattern. Oxaliplatin therapy showed beneficial results for approximately 1 week. Microscopic evaluation of synovitis during this period showed strong nuclear HMGB1 staining in the oxaliplatin treated animals with much lower quantities of extracellular HMGB1 when compared to control treated animals. Furthermore, cellular infiltration, as well as cartilage and bone damage, were all reduced in the oxaliplatin treated group. A dramatic and as yet unexplained clinical relapse occurred later in the oxaliplatin exposed animals, which coincided with a massive synovial tissue expression of extracellular HMGB1 in all treated animals. This rebound-like reaction was also accompanied by a significantly increased incidence of arthritis in the oxaliplatin treated group. These results indicate a distinct temporal and spatial relationship between the clinical course of disease and the cellular localization of HMGB1. Beneficial effects were noted when extracellular HMGB1 expression was low, while severe inflammation coincided with substantial extracellular synovial HMGB1 expression.


CONCLUSIONS
Therapeutic compounds like oxaliplatin and gold salts share a capacity to inhibit nuclear HMGB1 release and to ameliorate the course of synovial inflammation. These observations support the hypothesis that HMGB1 plays an important functional role in the pathogenesis of arthritis and may represent a novel target molecule for therapy.
Ostberg
Therese
T
Department of Woman and Child Health, Pediatric Rheumatology Research Unit, Karolinska Institutet/Karolinska University Hospital, 171 176 Stockholm, Sweden. Therese.Ostberg@ki.se
Wähämaa
Heidi
H
Palmblad
Karin
K
Ito
Norimasa
N
Stridh
Pernilla
P
Shoshan
Maria
M
Lotze
Michael T
MT
Harris
Helena Erlandsson
HE
Andersson
Ulf
U
D000818:Animals; D001169:Arthritis, Experimental / Q000139:chemically induced* / Q000378:metabolism*; D002358:Cartilage, Articular / Q000473:pathology; D002467:Cell Nucleus / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D024043:Collagen Type II; D024243:HMGB1 Protein / Q000378:metabolism*; D007274:Injections, Intraperitoneal; D008198:Lymph Nodes / Q000276:immunology / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008811:Mice, Inbred DBA; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D010047:Ovalbumin / Q000276:immunology; D000077150:Oxaliplatin; D013585:Synovitis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D013601:T-Lymphocytes / Q000473:pathology; D013997:Time Factors; D014018:Tissue Distribution
D024043:Collagen Type II; D024243:HMGB1 Protein; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D010047:Ovalbumin