探討脂聯素在類風濕性關節炎調控血管新生的作用機制

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Title:	探討脂聯素在類風濕性關節炎調控血管新生的作用機制 Exploring the role of adiponectin in angiogenesis of rheumatoid arthritis
Authors:	黃建中;Chien-Chung Huang
Contributors:	臨床醫學研究所博士班
Keywords:	類風濕性關節炎;脂聯素;血管新生;血管內皮生長因子;微小核醣核酸-106a-5p;rheumatoid arthritis;adiponectin;angiogenesis;vascular endothelial growth factor;miR-106a-5p
Date:	2019-06-24
Issue Date:	2019-11-11 09:19:56 (UTC+8)
Publisher:	中國醫藥大學
Abstract:	類風濕性關節炎是一種世界各地普遍的風濕疾病，它更是在台灣最盛行的一個自體免疫風濕疾患，類風濕性關節炎的特色表現是漸進式並對稱性的多發性關節炎，此疾病往往會造成骨頭的侵蝕和關節的變形，若沒有經過適當地治療，病患會因為持續的關節腫痛而逐漸喪失日常生活的能力，並可能在疾病的末期變成殘障。血管新生(angiogenesis)是類風濕性關節炎致病機轉中重要的一環，此疾病的血管新生過程會招引更多的白血球浸潤在關節滑液膜中，進而增加促發炎細胞激素和破壞性蛋白?的產生。脂聯素(adiponectin)是一種在血液中循環的荷爾蒙，其主要由脂肪細胞來分泌，同時是表現量最高的一種脂肪激素，越來越多的研究顯示，類風濕性關節炎的病患其血清和關節液中脂聯素的濃度和疾病活動度相關，而且脂聯素在此疾病中呈現促發炎性的特質，然而，關於脂聯素如何影響類風濕性關節炎血管新生的表現尚不完全清楚，因此這個研究的目的在於探討脂聯素作用在類風濕性關節炎血管新生的機制。 MH7A細胞源自於一種類風濕性關節炎滑液膜纖維母細胞的細胞株，我們利用此細胞進行實驗，發現脂聯素會隨著劑量和時間地遞增來加強血管內皮生長因子(vascular endothelial growth factor)的表現，並進而促進內皮前驅細胞(endothelial progenitor cells)的管形成作用(tube formation)和移行能力(migration)，同時藉由細胞實驗和雞胚胎尿絨毛膜(chorioallantoic membrane)模式及Matrigel plug模式測定活體實驗，我們證實這些促進血管新生的作用是經由MEK/ERK訊息傳遞路徑和抑制微小核醣核酸-106a-5p(miR-106a-5p)的表現所影響，此外，脂聯素是經過連結到脂聯素受體1(adiponectin receptor 1)之後產生後續促進血管新生作用，我們亦在膠原蛋白誘發關節炎(collagen-induced arthritis)的動物模式中，證實抑制脂聯素能顯著減緩腳掌腫脹和骨頭侵蝕的情形。綜合所述，我們的結果顯示脂聯素能刺激類風濕性關節炎滑液膜纖維母細胞分泌血管內皮生長因子，進而促進內皮前驅細胞的管形成作用和移行能力，這些促進血管新生的作用是經由連結到脂聯素受體1和後續MEK/ERK訊息傳遞路徑及抑制微小核醣核酸-106a-5p的表現所共同影響，這個以脂聯素為標的之抗血管新生策略，也許能作為有益於現行治療類風濕性關節炎的附加治療，這些需要更進一步的臨床研究。 Rheumatoid arthritis (RA) is a worldwide common rheumatic disease and it is the most prevalent autoimmune rheumatic disease in Taiwan. RA is characterized by progressive symmetric polyarthritis which would lead to bony erosions and joints deformity. Without adequate treatment, patients with RA could lose daily life abilities and become handicapped in the late time. Angiogenesis is one of the pivotal pathogenic mechanisms in RA. The angiogenic process in RA results in recruitment of more leukocytes into the synovium to promote proinflammatory cytokines and destructive proteases production. Adiponectin is a circulating hormone mainly secreted by adipocytes and has the highest expression level among all adipokines. Growing studies indicate that increased adiponectin levels in both serum and synovial fluid are associated with RA disease activity. Proinflammatory property of adiponectin in RA also has been elucidated. However, the effect of adiponectin on RA angiogenic manifestations has not been well understood. Thus, the aim of this study is to investigate the mechanism of adiponectin in RA angiogenesis. By using MH7A cells, the RA synovial fibroblast cell line, we found that adiponectin dose- and time-dependently enhances vascular endothelial growth factor (VEGF) expression. This would promote endothelial progenitor cells (EPCs) tube formation and migration activities. We proved these angiogenic reactions are through the MEK/ERK signaling pathway and downregulation of microRNA-106a-5p (miR-106a-5p) expression not only in vitro but also in vivo experiments with utility of chick chorioallantoic membrane (CAM) and Matrigel plug assay. Rather than adiponectin receptor 2 (AdipoR2), it is via adiponectin receptor 1 (AdipoR1) that adiponectin exerts angiogenic function in RA. In collagen-induced arthritis (CIA) mouse model, we demonstrated that inhibition of adiponectin could significantly ameliorate paw swelling and bone erosions. Taken together, our results indicate that adiponectin stimulates VEGF-dependent EPCs tube formation and migration in RA synovial fibroblasts. These angiogenic effects are mediated through the MEK/ERK signaling pathway, as well as miR-106a-5p downregulation by connecting to the AdipoR1. The anti-angiogenic strategy by targeting adiponectin might be beneficial as an add-on therapy with current standard treatments of RA. This deserves further clinical studies.
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