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系統識別號 U0026-1601201400493200
論文名稱(中文) 研究微小核醣核酸223在類風溼性關節炎及實驗性關節炎模式中的角色以及調控
論文名稱(英文) Study on the role and regulation of miR-223 in rheumatoid arthritis and experimental arthritis model
校院名稱 成功大學
系所名稱(中) 基礎醫學研究所
系所名稱(英) Institute of Basic Medical Sciences
學年度 102
學期 1
出版年 103
研究生(中文) 李原聰
研究生(英文) Yuan-Tsung Li
學號 S58991358
學位類別 博士
語文別 英文
論文頁數 92頁
口試委員 指導教授-吳昭良
口試委員-賴明德
口試委員-劉校生
口試委員-陳玉玲
口試委員-陳得源
口試委員-林季千
中文關鍵字 微小核醣核酸223  類風溼性關節炎  基因治療  Nuclear factor 1-A 
英文關鍵字 microRNA-223  Rheumatoid arthritis  Gene therapy  Nuclear factor 1-A. 
學科別分類
中文摘要 近來的研究發現微小核醣核酸(microRNA)在自體免疫疾病中扮演著重要的角色。而在其中,微小核醣核酸兩百二十三號(miR-223)被發現到在類風濕性關節炎的病人當中會有大量的表現,其大量表現又被指出與蝕骨細胞的分化有關連性。而蝕骨細胞正是造成關節遭到侵蝕的元凶。在此研究中我們測試了使用慢病毒載體表現miR-223之目標基因序列(miR-223T)藉以抑制miR-223之活性作為治療膠原蛋白誘導小鼠關節炎模式之策略的可行性。在類風溼性關節炎(RA)病人、退化性關節炎(OA)病人的檢體以及小鼠關節炎模式當中,即時定量反轉錄鏈鎖聚合酶反應(real-time RT-PCR)被使用來偵測miR-223的表現量。慢病毒載體攜帶miR-223之目標基因序列(LVmiR-223T)或是針對冷光基因的小髮夾核醣核酸(LVshLuc)以腹腔內注射的方式給予膠原蛋白誘導關節炎之小鼠。此治療之反應以及和疾病相關之骨質密度也被監測。miR-223的其中一個目標—NF-1A,以及macrophage colony-stimulating factor的受體(M-CSFR)之表現量也藉由即時定量反轉錄鏈鎖聚合酶反應(real-time RT-PCR)和免疫組織化學染色來偵測。蝕骨細胞則藉由耐酒石酸之酸性磷酸酵素(tartrate-resistant acid phosphatase, TRAP)染色來偵測。實驗結果顯示,miR-223在類風溼性關節炎病人的滑液膜(synovium)組織中比起退化性關節炎有大量的表現。在膠原蛋白誘導關節炎之小鼠也有發現一樣的現象。給予LVmiR-223T 可以有效地降低關節炎指數、抑制miR-223表現、減少蝕骨細胞分化以及骨頭的侵蝕。而抑制miR-223也會導致在小鼠滑液膜中NF1-A的表現量上升,M-CSFR的表現量下降。除此之外我們也進一步發現miR-223對於膠原蛋白誘導關節炎滑液纖維母細胞(CIA SF)的不正常增生扮演一個不可或缺的角色。當miR-223被抑制,CIA SF的增生也會因為Akt/mTOR訊息路徑被抑制而減慢。本研究為首次證明利用慢病毒載體抑制miR-223可以用以減緩小鼠關節炎疾病之嚴重性。此研究之結果更進一步提供抑制miR-223的活性作為類風溼性關節炎治療策略的可能性。
英文摘要 MicroRNAs (miRNAs) play roles in autoimmune diseases. MiRNA-223 (miR-223) is upregulated in rheumatoid arthritis (RA) patients and is involved in osteoclastogenesis that contributes to erosive disease. Here we tested the feasibility of using lentiviral vectors expressing the miR-223 target sequence (miR-223T) to suppress miR-223 activity as a therapeutic strategy in a mouse model of collagen-induced arthritis (CIA). Levels of miR-223 expression in the synovial tissue of RA and osteoarthritis (OA) patients as well as ankle joints of CIA mice were determined by quantitative RT-PCR. Lentiviral vectors expressing miR-223T (LVmiR-223T) or luciferase shRNA (LVshLuc) serving as a control vector were injected intraperitoneally into CIA mice. The treatment responses and disease-related bone mineral density were monitored. Levels of NFI-A, a direct target of miR-223, and macrophage colony-stimulating factor receptor (M-CSFR) critical for osteoclastogenesis were detected by immunohistochemistry and quantitative RT-PCR. Osteoclasts were assessed by TRAP staining. MiR-223 expression was significantly higher in the synovium of RA patients and ankle joints of CIA mice compared with OA patients and normal mice. LVmiR-223T reduced the arthritis score, histologic score, miR-223 expression, osteoclastogenesis, and bone erosion in CIA mice. Downregulation of miR-223 with concomitant increases in NFI-A levels and decreases in M-CSFR levels was detected in the synovium of LVmiR-223T-treated mice. We also found that miR-223 is essential for the hyperproliferation of CIA synovial fibroblasts (SFs). When miR-223 is suppressed, the proliferation of CIA SF is reduced through the downregulation of Akt/mTOR pathway. This report is the first to demonstrate that lentivirus-mediated silencing of miR-223 can reduce disease severity of experimental arthritis. Furthermore, our results implicate that inhibition of miR-223 activity may be further explored as a therapeutic strategy for patients with RA.
論文目次 Chinese Abstract I
Abstract III
List of figures and tables IX
Abbreviations XII
Introduction 1
Rheumatoid arthritis 1
Synovial fibroblasts in rheumatoid arthritis 2
Osteoclasts and rheumatoid arthritis 4
Microrna and rheumatoid arthritis 5
Mir-223 and rheumatoid arthritis 7
IL-23 and rheumatoid arthritis 8
Rationale and hypothesis 11
Specific aims 12
Materials and methods 13
Antibodies and recombinant proteins 13
Reagents and kits 15
Primers 16
Equipment and software 17
Clinical samples from RA and OA patients. 18
Culture and differentiation of bone marrow-derived macrophages (BMMs). 18
Quantification of miR-223, NF1-A, and M-CSFR. 18
Construction of lentiviral vectors. 19
Induction of CIA and gene therapy. 19
Histochemistry, immunohistochemistry, immunoblotting, and tartrate-resistant acid phosphatase (TRAP) staining. 20
Flow cytometry 21
ELISA for TRAP 21
In vivo detection of green fluorescence using IVISR imaging system 21
Isolation of synovial fibroblasts 22
Proliferation assay 22
Statistical analysis 22
Results 23
Increased microRNA-223 (miR-223) expression in the synovium tissue of patients with rheumatoid arthritis (RA) and in the ankle joints of mice with CIA. 23
Increased microRNA-223 expression and decreased nuclear factor 1 A (NF1-A) expression in the ankles of mice with collagen-induced arthritis. 23
Increased miR-223 expression and decreased NF1-A expression during osteoclasts differentiation 24
MiR-223T efficiently inhibit miR-223 in U937 monocytes 25
Knocking down the expression of miR-223 by LVmiR-223T reduces osteoclasts (OCs) differentiation from bone marrow-derived macrophages (BMMs). 25
LVmiR-223T infection ameliorates the symptoms of mice with CIA by knockdown of miR-223. 26
Knockdown of miR-223 decreases bone erosion in the CIA mice by repressing osteoclasts differentiation. 27
Increased microRNA-223 expression and proliferation in the synovial fibroblasts from mice with collagen-induced arthritis. 28
MiR-223 promotes the hyperproliferation of synovial fibroblasts from CIA mice through mTOR pathway. 28
Interleukine-23 (IL-23) promotes osteoclast differentiation, miR-223 expression, and is overexpressed in the collagen-induced arthritis mouse model. 29
DNA methyl transferase 1 (DNMT1) is a potential target for miR-223 in the synovial fibroblasts. 30
Discussion 32
Mir-223 is overexpressed and essential in RA and the CIA mouse model 32
MiR-223 promotes osteoclasts differentiation through downregulating NF1-A and upregulating M-CSFR 33
The regulations of NF1-A and M-CSFR in RA 33
MiR-223 may ameliorate CIA mouse symptoms by inhibiting myeloid cells proliferation and differentiation 35
MiR-223 is essential for the hyperproliferation of CIASF 35
MiR-223 promotes SF hyperproliferation through direct targeting FBXW7 and promoting mTOR pathway 36
MiR-223 may also inhibit NF1-A expression in synovial fibroblasts and promote mTOR pathway in osteoclast precursor cells 36
IL-23 may promote miR-223 expression through the activation of p-STAT4 37
Side effects of targeting miR-223 in RA 38
MiR-223 serves as a potential therapeutic target for RA 39
Figures 41
Conclusion 80
References 81
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