Research Papers: Pathology:

Inhibition of angiogenesis by arsenic trioxide via TSP-1–TGF-β1-CTGF–VEGF functional module in rheumatoid arthritis

Juan Zhang, Chunling Li, Yining Zheng, Zhiguo Lin, Yue Zhang and Zhiyi Zhang _

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Oncotarget. 2017; 8:73529-73546. https://doi.org/10.18632/oncotarget.19867

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Juan Zhang1,*, Chunling Li1,*, Yining Zheng1, Zhiguo Lin1, Yue Zhang1 and Zhiyi Zhang1

1 Department of Rheumatology, The First Affiliated Hospital, Harbin Medical University, Nan Gang, Harbin, China

* These authors have contributed equally to this work

Correspondence to:

Zhiyi Zhang, email:

Yue Zhang, email:

Keywords: angiogenesis, arsenic trioxide, rheumatoid arthritis, TGF-β1, VEGF, Pathology Section

Received: January 30, 2017 Accepted: July 11, 2017 Published: August 03, 2017


Angiogenesis is a critical factor for rheumatoid arthritis (RA). Although anti-TNF biologics work effectively on some RA patients, concerns have been raised about the possible increased development of malignancies alongside such treatments. Arsenic trioxide (As2O3) has attracted worldwide attention and has been reported to treat some cancers. However, the effects of As2O3 on angiogenesis in the RA synovium remain unclear. Here, we report a systematic increased expression of TSP-1, TGF-β1, CTGF and VEGF in supernatants of a RA fibroblast-like synoviocytes (RA-FLS) and human dermal microvascular endothelial cells (HDMECs) co-culture compared with those from a normal human fibroblast-like synoviocytes (NH-FLS) and HDMECs co-culture. This increased expression may up-regulate endothelial tube formation and transwell migration, as well as microvessel sprouting in ex vivo aortic ring assay. These networked angiogenic factors mainly form a functional module regulating angiogenesis in the RA synovium. We show that As2O3 inhibits angiogenesis in the collagen-induced arthritis (CIA) synovium and consequently arthritis severity via significant suppression of TSP-1, TGF-β1, CTGF and VEGF expression in the CIA synovium, plus in the RA-FLS and HDMECs co-culture as well as NH-FLS and HDMECs co-culture system along with the presence or absence of TNF-α treatment. Thus As2O3 has a significant anti-angiogenesis effect on the RA-FLS and CIA synovium via its inhibition of the RA angiogenic functional module of TSP-1, TGF-β1, CTGF and VEGF and may have a potential for treating RA beyond cancer therapy.

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