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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\u2010inducible factor (HIF)\u20101\u03b1 to mediate angiogenesis in RA synovium. HIF\u20101\u03b1 mRNA levels and activities in synovial fibroblasts from RA patients were enhanced by HMGB1. Pharmacological inhibition of TLR4 and NF\u2010kappaB activation blocked the HMGB1\u2010dependent upregulation of HIF\u20101\u03b1 mRNA expression and its activity, suggesting the involvement of transcriptional regulation. HMGB1 stimulated expression of vascular endothelial growth factor (VEGF), and inhibition of HIF\u20101\u03b1 attenuated HMGB1\u2010induced VEGF. Conditioned media derived from HMGB1\u2010stimulated synovial fibroblasts enhanced tube formation in human microvascular endothelial cells by upregulating HIF\u20101\u03b1. In the joint tissues of mice with collagen\u2010induced arthritis, treatment with anti\u2010HMGB1 neutralizing antibody prevented blood vessel formation in association with decreased expression of HIF\u20101\u03b1. These observations support the idea that increased HMGB1 induces an extension of inflamed synovium by accelerating angiogenesis in RA through enhancement of HIF\u20101\u03b1 activation. Therefore, inhibition of HMGB1 could prove beneficial for the treatment of angiogenesis in RA.<\/jats:p>","DOI":"10.1002\/eji.201444908","type":"journal-article","created":{"date-parts":[[2014,12,24]],"date-time":"2014-12-24T15:40:30Z","timestamp":1419435630000},"page":"1216-1227","source":"Crossref","is-referenced-by-count":115,"title":["HMGB1 induces angiogenesis in rheumatoid arthritis via HIF\u20101\u03b1 activation"],"prefix":"10.1002","volume":"45","author":[{"given":"So Youn","family":"Park","sequence":"first","affiliation":[{"name":"Medical Research Center for Ischemic Tissue Regeneration Pusan National University Gyeongnam Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sung Won","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine College of Medicine Dong\u2010A University Busan Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hye Young","family":"Kim","sequence":"additional","affiliation":[{"name":"Medical Research Center for Ischemic Tissue Regeneration Pusan National University Gyeongnam Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Won Suk","family":"Lee","sequence":"additional","affiliation":[{"name":"Medical Research Center for Ischemic Tissue Regeneration Pusan National University Gyeongnam Republic of Korea"},{"name":"Department of Pharmacology School of Medicine Pusan National University Gyeongnam Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ki Whan","family":"Hong","sequence":"additional","affiliation":[{"name":"Medical Research Center for Ischemic Tissue Regeneration Pusan National University Gyeongnam Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chi Dae","family":"Kim","sequence":"additional","affiliation":[{"name":"Medical Research Center for Ischemic Tissue Regeneration Pusan National University Gyeongnam Republic of Korea"},{"name":"Department of Pharmacology School of Medicine Pusan National University Gyeongnam Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2015,1,15]]},"reference":[{"issue":"2","key":"e_1_2_7_2_1","doi-asserted-by":"crossref","first-page":"ii60","DOI":"10.1136\/ard.62.suppl_2.ii60","article-title":"Angiogenesis as a target in rheumatoid arthritis","volume":"62","author":"Koch A. 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