title: Anti-angiogenic effect of triptolide in rheumatoid arthritis by targeting angiogenic cascade.
abstract: Rheumatoid arthritis (RA) is characterized by a pre-vascular seriously inflammatory phase, followed by a vascular phase with high increase in vessel growth. Since angiogenesis has been considered as an essential event in perpetuating inflammatory and immune responses, as well as supporting pannus growth and development of RA, inhibition of angiogenesis has been proposed as a novel therapeutic strategy for RA. Triptolide, a diterpenoid triepoxide from Tripterygium wilfordii Hook F, has been extensively used in treatment of RA patients. It also acts as a small molecule inhibitor of tumor angiogenesis in several cancer types. However, it is unclear whether triptolide possesses an anti-angiogenic effect in RA. To address this problem, we constructed collagen-induced arthritis (CIA) model using DA rats by the injection of bovine type II collagen. Then, CIA rats were treated with triptolide (11-45 µg/kg/day) starting on the day 1 after first immunization. The arthritis scores (P<0.05) and the arthritis incidence (P<0.05) of inflamed joints were both significantly decreased in triptolide-treated CIA rats compared to vehicle CIA rats. More interestingly, doses of 11~45 µg/kg triptolide could markedly reduce the capillaries, small, medium and large vessel density in synovial membrane tissues of inflamed joints (all P<0.05). Moreover, triptolide inhibited matrigel-induced cell adhesion of HFLS-RA and HUVEC. It also disrupted tube formation of HUVEC on matrigel and suppressed the VEGF-induced chemotactic migration of HFLS-RA and HUVEC, respectively. Furthermore, triptolide significantly reduced the expression of angiogenic activators including TNF-α, IL-17, VEGF, VEGFR, Ang-1, Ang-2 and Tie2, as well as suppressed the IL1-β-induced phosphorylated of ERK, p38 and JNK at protein levels. In conclusion, our data suggest for the first time that triptolide may possess anti-angiogenic effect in RA both in vivo and in vitro assay systems by downregulating the angiogenic activators and inhibiting the activation of mitogen-activated protein kinase downstream signal pathway.
authors.affiliation: Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China.
authors.forename: Xiangying
authors.initials: X
authors.lastname: Kong
authors.forename: Yanqiong
authors.initials: Y
authors.lastname: Zhang
authors.forename: Chunfang
authors.initials: C
authors.lastname: Liu
authors.forename: Wei
authors.initials: W
authors.lastname: Guo
authors.forename: Xiangbin
authors.initials: X
authors.lastname: Li
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Su
authors.forename: Hongye
authors.initials: H
authors.lastname: Wan
authors.forename: Yanqun
authors.initials: Y
authors.lastname: Sun
authors.forename: Na
authors.initials: N
authors.lastname: Lin
mesh_terms: D043924:Angiogenesis Modulating Agents / Q000378:metabolism; D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D004224:Diterpenes / Q000494:pharmacology*; D004338:Drug Combinations; D004852:Epoxy Compounds / Q000494:pharmacology; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007797:Laminin / Q000378:metabolism; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010616:Phenanthrenes / Q000494:pharmacology*; D011509:Proteoglycans / Q000378:metabolism; D051381:Rats; D013583:Synovial Membrane / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D043924:Angiogenesis Modulating Agents; D004224:Diterpenes; D004338:Drug Combinations; D004852:Epoxy Compounds; D007797:Laminin; D010616:Phenanthrenes; D011509:Proteoglycans; D042461:Vascular Endothelial Growth Factor A; C059485:matrigel; C001899:triptolide; D003094:Collagen; D020928:Mitogen-Activated Protein Kinases