血管增生與類風濕性關節炎

Angiogenesis in rheumatoid arthritis

類風濕性關節炎是一種慢性發炎性自體免疫性疾病，其致病原因未明。此種疾病主要特徵是關節及周圍組織持續性的發炎，滑液膜內新血管形成及滑液膜細胞增生而形成所謂血管翳，及進一步會導致關節永久性的破壞. 新血管形成 — 血管新生 （angiogenesis） — 已經被認為是滑液膜持續性發炎與疾病進展重要的致病機轉。在一些研究中已發現類風濕性關節炎內滑液膜之持續性發炎與促進血管新生因子過度表現有相關，以及在動物實驗中也發現抑制血管新生可使關節炎的症狀趨緩。近年來，在RA之滑膜組織發現除了可由既有的血管之中萌芽形成新生血管，也得以從骨髓組織動員出內皮原生細胞（endothelial progenitor cells）再演化而成新血管 （vasculogenesis）。血管內皮生長因子（vascular endothelial growth factor, VEGF）是眾多促進血管新生因子當中啟動血管生成功能最顯著的一種，且在血管新生過程中扮演重要角色，而且可以促進滑液膜的血管新生。在今日，血管生成抑制劑，其目標鎖定在強勁的血管內皮生長因子上面。目前已上市的商業產品“Bevacizumab”是一種人體化的抗血管內皮生長因子單株抗體（humanized monoclonal anti-VEGF antibody）。Bevacizumab在 2004年美國食品藥物管理局 （FDA） 的認證上只侷限於大腸直腸癌方面而已，但至今仍有許多抑制血管增生的新藥正在進行臨床試驗。因此可見的未來，預期這些新藥也可能用來治療類風濕性關節炎。最近的動物實驗中，介白質-13（interleukin-13）、甲硫丁氨酸氨基肽酶抑制劑（PPI-2458）, 內皮細胞阻斷劑（endostatin）、去乙醯基酵素抑制劑（FK 228），都顯示有抑制血管新生的效果。另外，一些天然植物成份如青藤鹼（sinomenine）、漢黃芩素 （wogonin） 也被發現有抑制血管增生的療效。在這篇文章中，我們將論述血管新生在類風濕性關節炎致病機轉角色方面的最新信息以及抑制血管新生的藥物在治療類風濕性關節炎方面的展望。

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease with unknown etiology, characterized by perpetuated inflammation, pannus formation, and joint destruction. The formation of new blood vessels – termed 'angiogenesis' – is now recognized as a key event in the perpetuation of RA synovitis. There is plenty of evidence supporting this hypothesis, including the expression of proangiogenic factors in synovial tissue and the inhibition of angiogenesis ameliorating the disease severity in animal models of arthritis. Recent studies have shown that neovasculature in RA synovium not only arises through the budding of pre-existing vessels (angiogenesis), but also results from the recruitment of blood vessels in a bone marrow-origin progenitor population (vasculogenesis). Although many pro-angiogenic factors have been identified, vascular endothelial growth factor (VEGF) has a central role in the angiogenic process. VEGF is also involved in endothelial progenitor cells mobilization. The US Food and Drug Administration (FDA) approved the anti-VEGF antibody, bevacizumab, the first angiogenesis inhibitor, for metastatic colorectal cancer in 2004. Numerous clinical trials are testing this with various angiogenic diseases. There are expectations that oncologic therapies that block VEGF activity will also be applicable to RA in the future, to reduce synovial angiogenesis and pannus proliferation. More recently, interleukin-13 gene therapy in a rat model of RA, and some other novel agents in animal studies, such as PPI-2458, endostatin, and FK 228, have all showed anti-angiogenic effects. In addition, some natural compounds, such as sinomenine and wogonin, can inhibit angiogenesis. The present review will update our understanding of the role of angiogenesis in RA, and the prospects for anti-angiogenic therapy in RA.