Methionine aminopeptidase-2 blockade reduces chronic collagen-induced arthritis: potential role for angiogenesis inhibition.
Methionine aminopeptidase-2 blockade reduces chronic collagen-induced arthritis: potential role for angiogenesis inhibition.
复制标题
蛋氨酸氨基肽酶-2封闭可减少慢性胶原蛋白诱导的关节炎：血管生成抑制的潜在作用。
DOI：
10.1186/ar2340
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发表时间：
2007
影响因子：
4.9
通讯作者：
Paleolog, Ewa M.
中科院分区：
文献类型：
--
作者：
Bainbridge, John;Madden, Leigh;Essex, David;Binks, Michael;Malhotra, Rajneesh;Paleolog, Ewa M.
甲硫氨酸氨肽酶-2（MetAP-2）被认为在人类内皮细胞增殖中发挥重要作用，因此在炎症和癌症中提供了有价值的靶标。类风湿性关节炎（RA）是一种与滑膜血管生成增加相关的慢性炎症性疾病，因此是血管生成抑制剂的潜在治疗靶点。我们研究了PPI-2458（一种选择性不可逆的MetAP-2抑制剂）在RA疾病模型（即小鼠急性和慢性胶原诱导性关节炎（CIA））中的应用。虽然急性CIA是一种双相性疾病，但用鼠II型胶原诱导的CIA表现为慢性复发性关节炎，并且更接近于RA的病程。我们的研究表明，PPI-2458能够减少急性和慢性CIA模型中关节炎的临床体征。这种关节炎的减少是由关节炎症和破坏的减少所抵消的。详细的作用机制研究表明，PPI-2458在体外抑制人内皮细胞增殖和血管生成，而不影响炎性细胞因子的产生。此外，我们还研究了从人RA滑膜细胞培养物中释放的炎性细胞因子和趋化因子，并观察到PPI-2458对细胞因子和趋化因子的自发表达没有影响，甚至对血管生成分子血管内皮生长因子（VEGF）也没有影响。这些结果突出了MetAP-2作为RA治疗干预的良好候选者。
The enzyme methionine aminopeptidase-2 (MetAP-2) is thought to play an important function in human endothelial cell proliferation, and as such provides a valuable target in both inflammation and cancer. Rheumatoid arthritis (RA) is a chronic inflammatory disease associated with increased synovial vascularity, and hence is a potential therapeutic target for angiogenesis inhibitors. We examined the use of PPI-2458, a selective non-reversible inhibitor of MetAP-2, in disease models of RA, namely acute and chronic collagen-induced arthritis (CIA) in mice. Whilst acute CIA is a monophasic disease, CIA induced with murine collagen type II manifests as a chronic relapsing arthritis and mimics more closely the disease course of RA. Our study showed PPI-2458 was able to reduce clinical signs of arthritis in both acute and chronic CIA models. This reduction in arthritis was paralleled by decreased joint inflammation and destruction. Detailed mechanism of action studies demonstrated that PPI-2458 inhibited human endothelial cell proliferation and angiogenesis in vitro, without affecting production of inflammatory cytokines. Furthermore, we also investigated release of inflammatory cytokines and chemokines from human RA synovial cell cultures, and observed no effect of PPI-2458 on spontaneous expression of cytokines and chemokines, or indeed on the angiogenic molecule vascular endothelial growth factor (VEGF). These results highlight MetAP-2 as a good candidate for therapeutic intervention in RA.
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影响因子：
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