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研究生:張主龍
研究生(外文):Chu-Lung Chang
論文名稱:L-Caldesmon可透過改變細胞延展與黏滯力進而影響破骨細胞分化
論文名稱(外文):L-Caldesmon Dependent Mechanical Changes of Cell Spreading and Adhesion Force in Osteoclastogenesis
指導教授:劉英明
口試委員:施明智邱繡河龍鳳娣陳慧毅
口試日期:2017-07-21
學位類別:碩士
校院名稱:國立中興大學
系所名稱:生命科學系所
學門:生命科學學門
學類:生物學類
論文種類:學術論文
論文出版年:2017
畢業學年度:105
語文別:中文
論文頁數:83
中文關鍵詞:Caldesmon (CaD)破骨細胞分化RANKLTRAP原子力顯微鏡 (AFM)細胞融合
外文關鍵詞:Caldesmon (CaD)osteoclastogenesisRANKLTRAPAtomic Force Microscopy (AFM)cell fusion
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Caldesmon (CaD) 是一種肌動調節蛋白,有兩種蛋白異構物,分別為高分子型 h-CaD,以及低分子型 l-CaD;這兩種CaD蛋白異構物皆能穩定肌動蛋白絲並使其不被切割蛋白所瓦解。此外CaD還能抑制肌動球蛋白ATP酶的活性,甚至抑制由Arp2/3複合蛋白所調控的肌動蛋白聚合反應。先前文獻指出:l-CaD參與許多細微結構,包括足體結構的分子重塑,與骨骼肌細胞的分化。在預備實驗中,也發現l-CaD的基因及蛋白表現皆在破骨細胞分化期間有顯著提升;然而,目前有關l-CaD如何影響破骨細胞分化與細胞融合機制尚未明確。為了瞭解l-CaD如何調控破骨細胞分化機制,利用培養轉殖小鼠Raw264.7巨噬細胞株使其表現融合質體EGFP-l-CaD外源基因,再以分化因子RANKL刺激,最後觀察l-CaD過表現對破骨細胞分化之影響。結果顯示:轉殖EGFP-l-CaD的細胞增加破骨細胞分化與細胞融合的潛能,並且增加破骨細胞指標基因表現,包括:c-Fos、NFATc1、CTSK、TRAP;顯示增加外源l-CaD表現會促使提升破骨細胞分化的能力。另外,經由基因緘默l-CaD處理分化前的細胞,其破骨細胞分化的效率明顯受到抑制。為了進一步了解l-CaD如何調節破骨細胞分化與細胞融合所產生的細胞機械特性的變化,利用原子力顯微鏡來檢測分化中的破骨細胞表面形貌分佈與細胞表面的黏滯力。量測細胞表面形貌變化可以提供細胞外展的特性,而細胞表面的黏滯力的測量可以估算細胞融合的能力。結果發現:過表現l-CaD的分化細胞,其外緣延展能力明顯增加;另外,細胞外緣延展的區域的黏滯力都有提升的現象;反之,si l-CaD基因緘默的細胞,相對的細胞區域也都有明顯的減少。因此,l-CaD調節破骨細胞的分化程度可能經由改變細胞骨架的重組,進而影響細胞延展與表面的黏滯力,並影響破骨細胞融合的效率。
Caldesmon (CaD) is an actin regulator, expressing two isoforms in smooth muscle cells (h-CaD) and non-muscle cells (l-CaD), respectively. Both isoforms of CaD are capable of stabilizing actin filaments against actin-severing proteins, inhibiting actomyosin ATPase activity, and inhibiting Arp2/3-mediated actin polymerization. However, little is known about the role of l-CaD in the control of cell-cell fusion in osteoclastogenesis. To determine the functional role of the increased l-CaD expression in osteoclastogenesis, Raw264.7 cells transfected with fusion DNA constructs containing EGFP and l-CaD and followed by RANKL induction were investigated. In comparison with no transfection, overexpressing l-CaD significantly increased osteoclastogenic gene expressions for CTSK, c-fos, NFATc1, and beta 3 integrin in cells. Analyses with TRAP staining also indicated that l-CaD overexpression could accelerate osteoclast (OC) cell differentiation. On the other hand, si l-CaD decreased the potential for RANKL-induced OC differentiation. To determine whether l-CaD is involved in modulating cell-cell profusion in osteoclastogenesis, Atomic Force Microscopy (AFM) was used to resolve the mechanical changes of cell spreading and adhesion in RANKL-induced OCs with or without l-CaD overexpression. Cell spreading is determined by height scanning area, where the percentage of outmost and peripheral areas to total scanning area represents the tendency of cell spreading out of the center. In addition, cell-cell fusion was measured by the cell fusion index. Our data obtained showed that overexpression of l-CaD increased the cell-spreading and adhesion force that might facilitate cell-cell fusion into multinucleate OCs. Clearly, the regulation of l-CaD expression is important event for osteoclastogenesis.
摘要 ........................................................i
Abstract ...................................................ii
目錄 ......................................................iii
表目錄 .....................................................vi
圖目錄 ....................................................vii
附錄 .....................................................viii

一、 前言 ................................................1
(一) 研究背景與目的 ......................................1
(二) 巨噬細胞的特性與Raw264.7細胞株.......................3
(三) 破骨細胞分化 (osteoclast) 與破骨細胞 ................4
1. 分化特徵 ............................................4
2. 破骨細胞分化的相關因子及路徑 ........................6
(四) 足體 (podosome) .....................................8
(五) Caldesmon ...........................................9
(六) 研究動機與假說 .....................................10

二、 材料與方法 .........................................11
(一) Raw264.7 細胞之培養 ................................11
(二) 細胞生長曲線 .......................................11
1. 細胞計數 ...........................................11
2. MTT檢測細胞數倍增時間 (population doubling time,PDT) ..11
3. MTT檢測細胞對G418之耐受程度 ........................12
(三) 誘導Raw264.7細胞分化成破骨細胞並觀察型態 ...........12
(四) 細胞染色 ...........................................12
1. DAPI染色 ...........................................12
2. TRAP染色 ...........................................13
(五) 細胞轉染 ...........................................13
1. L-CaD質體DNA及siCaD (short interfering RNA) 轉染 ...13
2. 轉染細胞篩選及放大 .................................14
(六) 細胞基因表現檢測 ...................................15
1. Total RNA萃取 ......................................15
2. mRNA反轉錄 (reverse transcription) 合成cDNA ........16
3. 即時定量聚合酶連鎖反應 (real-time quantitative PCR).16
(七) 細胞蛋白表現檢測 ...................................17
1. 細胞蛋白萃取及定量 .................................17
2. 西方墨點法 (Western blot) ..........................18
(八) 原子力顯微鏡 (atomic force microscope) 觀察細胞之形貌與應力 ..19
1. 成像原理 ...........................................19
2. 成像應用 ...........................................20
3. 檢體製備 ...........................................20
4. 資料分析 ...........................................21
(九) 再吸收試驗 (resorption assay) ......................22
(十) 統計分析 (statistical analysis) ....................22

三、 預備實驗結果 .......................................25
(一) 誘導Raw264.7巨噬細胞分化成破骨細胞 .................25
1. 細胞分化型態變化及TRAP活性檢測 .....................25
2. 分化相關基因表現 ...................................27
(二) L-CaD在破骨細胞分化過程中之表現狀況 ................29
(三) 研究方向與策略 .....................................30

四、 實驗結果 ...........................................31
(一) 探討l-CaD對破骨細胞分化之影響 ......................31
1. L-CaD overexpression ...............................31
2. Si l-CaD ...........................................35
3. L-CaD對破骨細胞再吸收程度之改變 ....................40
(二) L-CaD對破骨細胞融合之影響 ..........................42

五、 討論 ...............................................48
(一) L-CaD與破骨細胞分化之關係 ..........................48
1. L-CaD受到相關轉錄因子之調控 ........................48
2. L-CaD影響相關轉錄因子之表現 ........................49
(二) L-CaD對於破骨細胞再吸收構造之探討 ..................50
1. L-CaD可能幫助足體在細胞中定位 ......................50
2. L-CaD對足體結構形成之影響 ..........................50
3. 足體對破骨細胞移動與再吸收之影響 ...................51
(三) L-CaD影響破骨細胞形貌與融合之關聯 ..................52
1. L-CaD對破骨細胞表面形貌及應力之影響 ................52
2. 細胞延展與黏滯力對細胞融合之探討 ...................53

六、 結論 ...............................................54
參考文獻 ...................................................55
附錄資料 ...................................................66
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