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.