類風濕性關節炎是一種慢性的關節疾病，其特徵為關節內有大量增生的滑膜組織，單核球的浸潤以及關節軟骨的破壞。大量增生的滑膜組織會導致血管翳的生成，進而逐漸侵蝕軟骨，造成關節的損傷。血管新生是形成血管翳所必須的，同時也是類風濕性關節炎最早形成的病理特徵。在本研究中，我們使用攜帶PTEN基因的腺病毒(命名為Ad-PTEN)，嘗試去治療大鼠關節炎模式。PTEN是一個腫瘤抑制因子，具有拮抗PI3 kinase磷酸化的功能，過量的表現PTEN會抑制細胞的增生以及促進細胞凋亡，除此之外，PTEN也能調節由VEGF對血管內皮細胞所造成的影響以及血管新生的作用。我們觀察到在類風濕性關節炎病人的滑液纖維母細胞(RASF)中，其VEGF分泌量以及細胞增生速度在Ad-PTEN感染後都明顯下降，且造成細胞凋亡，而感染Ad-LacZ的控制組是沒有影響的。同時，在感染Ad-PTEN的內皮細胞中，也觀察到細胞增生速度下降。動物模式中發現，相較於施打Ad-LacZ的控制組，預防性的在踝關節內施打Ad-PTEN的確使類風濕性關節炎的症狀減緩。而且觀察到相較於控制組，治療組的微血管密度明顯較低。因此我們認為PTEN的療效不僅可抑制RASF的增生，同時也透過降低RASF VEGF的分泌量以及血管內皮細胞的增生速度，來抑制血管新生，達到預防大鼠關節炎的效果。

Rheumatoid arthritis (RA) is a chronic joint disease characterized by hyperplasia of synovium, excessive infiltration of mononuclear cells, and extensive destruction of the articular cartilage. Hyperplasia of synovium leads to formation of pannus which destroys cartilage and bone in the affected joint. Angiogenesis, the formation of new blood vessels, is one of the earliest histopathologic findings in RA and appears to be necessary for pannus development. In this study, an adenoviral vector encoding PTEN (phosphatase and tensin homology deleted from chromosome 10), designated Ad-PTEN, was generated for gene therapy in the rat collagen-induced arthritis model. PTEN is a tumor suppressor that antagonizes the PI3 kinase (PI3K) pathway. Overexpression of PTEN suppresses cell proliferation and enhances apoptosis. Furthermore, PTEN can regulate VEGF-mediated endothelial cellular responses and angiogenesis. We observed that Ad-PTEN treatment reduced VEGF production, cell proliferation and enhanced apoptosis in the synovial fibroblasts from RA patients (RASF), whereas Ad-LacZ, a control adenoviral vector encoding β-galactosidase, had no effects. In cultured endothelial cells, PTEN overexpression also suppressed the cell proliferation. Moreover, prophylactic intraarticular injection of Ad-PTEN into the ankle joints of arthritic rats reduced the severity of arthritis, compared with those treated with Ad-LacZ. Decreased microvessel density within the joint tissue was observed in the Ad-PTEN-treated group compared with the Ad-LacZ-treated group. Taken together, these results suggest that the prophylactic effects of Ad-PTEN in CIA may be attributable, at least in part, to the down-regulation of cell proliferation in RASF and endothelial cells, and VEGF secretion in RASF.

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