title: HMGB1 induces angiogenesis in rheumatoid arthritis via HIF-1α activation.
abstract: High-mobility group box protein 1 (HMGB1), a nonhistone nuclear protein and a cytokine mediator, is implicated in the pathogenesis of rheumatoid arthritis (RA). Extracellular HMGB1 binds to its receptors and triggers downstream signal cascade leading to the perpetuation of synovitis and local tissue invasion. Here, we investigated a novel role of HMGB1 in regulating hypoxia-inducible factor (HIF)-1α to mediate angiogenesis in RA synovium. HIF-1α mRNA levels and activities in synovial fibroblasts from RA patients were enhanced by HMGB1. Pharmacological inhibition of TLR4 and NF-kappaB activation blocked the HMGB1-dependent upregulation of HIF-1α mRNA expression and its activity, suggesting the involvement of transcriptional regulation. HMGB1 stimulated expression of vascular endothelial growth factor (VEGF), and inhibition of HIF-1α attenuated HMGB1-induced VEGF. Conditioned media derived from HMGB1-stimulated synovial fibroblasts enhanced tube formation in human microvascular endothelial cells by upregulating HIF-1α. In the joint tissues of mice with collagen-induced arthritis, treatment with anti-HMGB1 neutralizing antibody prevented blood vessel formation in association with decreased expression of HIF-1α. These observations support the idea that increased HMGB1 induces an extension of inflamed synovium by accelerating angiogenesis in RA through enhancement of HIF-1α activation. Therefore, inhibition of HMGB1 could prove beneficial for the treatment of angiogenesis in RA.
authors.affiliation: Medical Research Center for Ischemic Tissue Regeneration, Pusan National University, Gyeongnam, Republic of Korea.
authors.forename: So Youn
authors.initials: SY
authors.lastname: Park
authors.forename: Sung Won
authors.initials: SW
authors.lastname: Lee
authors.forename: Hye Young
authors.initials: HY
authors.lastname: Kim
authors.forename: Won Suk
authors.initials: WS
authors.lastname: Lee
authors.forename: Ki Whan
authors.initials: KW
authors.lastname: Hong
authors.forename: Chi Dae
authors.initials: CD
authors.lastname: Kim
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D001169:Arthritis, Experimental; D001172:Arthritis, Rheumatoid / Q000473:pathology*; D042783:Endothelial Cells / Q000378:metabolism; D004789:Enzyme Activation; D005260:Female; D024243:HMGB1 Protein / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D008875:Middle Aged; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D009389:Neovascularization, Pathologic / Q000473:pathology*; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering; D013583:Synovial Membrane / Q000098:blood supply*; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis
chemical_list: D057134:Antibodies, Neutralizing; C497442:HIF1A protein, human; D024243:HMGB1 Protein; C585491:HMGB1 protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016328:NF-kappa B; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A
keywords: Fibroblast; HIF-1α; HMGB1; Rheumatoid arthritis; angiogenesis