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研究生:林靖汶
研究生(外文):Jin-Wen Lin
論文名稱:以細胞及動物模式探討礦物元素硒對於預防和緩解退化性關節炎之效用與機轉
論文名稱(外文):Study on the prevention of selenium against osteoarthritis in vitro and in vivo
指導教授:張基隆張基隆引用關係
指導教授(外文):Kee-Lung Chang
口試委員:蘇淑惠張文燦
口試委員(外文):Shu-Hui SuWen-Tsan Chang
學位類別:碩士
校院名稱:高雄醫學大學
系所名稱:醫學研究所碩士班
學門:醫藥衛生學門
學類:醫學學類
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:170
中文關鍵詞:退化性關節炎礦物元素硒抗氧化麩胱甘肽
外文關鍵詞:osteoarthritisseleniumantioxidantglutathione
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退化性關節炎(Osteoarthrts, OA)為中老年人最常見的關節疾病,起因於軟骨細胞分泌發炎細胞激素(cytokines)和活性氧化物質(reactive oxygen species, ROS),進而刺激關節軟骨細胞死亡及軟骨基質流失,導致關節疼痛甚至失能。礦物元素硒(selenium, Se)為必需微量礦物元素,已知具有抗氧化能力,但能否藉此預防軟骨細胞損傷仍未明。因此本研究將以細胞(in vitro)和動物(in vivo)實驗,探討亞硒酸鈉(sodium selenite, Na2SeO3)改善退化性關節炎之能力與機制。
細胞實驗結果顯示,亞硒酸鈉(Na2SeO3) 300 nM能有效抑制碘醋酸鈉(MIA)所導致的軟骨細胞死亡,並經由啟動Nrf2轉錄作用,促使合成麩胱甘肽(glutathione, GSH)相關酵素GCLC (glutamate-cysteine ligase catalytic subunit)、GCLM (glutamate-cysteine ligase modifier subunit)及GSS (glutathione synthetase)等基因表現,並提升抗氧化物質麩胱甘肽、超氧化物歧化酶(superoxidase dismutase, SOD)、麩胱甘肽過氧化酶(glutathione peroxidase, GPx)和麩胱甘肽還原酶(glutathione reductase, GR)等含量表現增加,達到清除細胞內過多活性氧化物質,並降低發炎性細胞激素及基質蛋白質分解酶表現,藉此預防軟骨基質糖胺聚醣(glycosaminoglycans, GAGs)的流失;由動物結果顯示,餵食亞硒酸鈉(Na2SeO3)或合併給予合成麩胱甘肽所需胺基酸
包含麩氨酸(glutamate)、半胱氨酸(cysteine)及甘氨酸(glycine)兩週後,可有效緩解軟骨磨損,此外,硒亦可提升大鼠血清中的麩胱甘肽和軟骨基質生成蛋白(procollagen I intact N-terminal propeptide, PINP),並抑制發炎性細胞激素的表現。
綜合上述結果可知硒(Se)可藉由提升抗氧化能力,以清除軟骨細胞內過多的活性氧化物質(ROS)和抑制發炎,達到預防軟骨細胞死亡及軟骨基質流失,進而改善退化性關節炎之功效。
Osteoarthritis (OA), one of the most common joint diseases, causes pain and disability among the elderly due to unusual productions of inflammatory cytokines and reactive oxygen species (ROS) by chondrocyte. These elevated factors were proposed to induce chondrocyte death and cartilage matrix destruction. Selenium (Se), an essential trace element, plays an important role in protection against oxidative damage in tissue. It is still unknown whether Se can resist the oxidative stress of chondrocyte injury or not. This study investigated the benefits of Se treatment with OA in vitro and in vivo.
Results of in vitro study showed 300 nM Se treatment could prevent SW1353 cell death from MIA damage and activate Nrf-2 pathway to promote gene expression of glutathione (GSH) synthesis related enzymes such as glutamate-cysteine ligase catalytic subunit (GCLC), glutamate- cysteine ligase modifier subunit (GCLM), and glutathione synthetase (GSS). In addition, glutathione, superoxide dismutase (SOD), glutathione peroxidases (GPx), and glutathione reductases (GR) expression also elevated to eliminate excessive ROS producton then decrease inflammatory cytokines, matrix proteases, and glycosaminoglycans (GAGs) loss. Results of in vivo study showed MIA-induced cartilage loss in Wistar rats could be lessened by Se treatment alone or combined with glutamate, cysteine, and glycine by oral gavage after 2 weeks. In addition, Se-treated rats had increased glutathione (GSH) and procollagen I intact N-terminal propeptide (PINP) synthesis then decreased the expression of pro-inflammatory cytokines of serum.
These results suggest that Se might protect chondrocytes from MIA-induced cell death and cartilage loss by increasing anti-oxidant capacity to remove ROS and inhibit inflammation then improve osteoarthritis.
壹、 中文摘要....................1
貳、 英文摘要....................3
參、 緒論......................5
一、 關節....................5
(一) 纖維性關節...................5
(二) 軟骨性關節...................5
(三) 滑膜性關節...................6
二、 退化性關節炎..................10
(一) 退化性關節炎之流行病學.............10
(二) 退化性關節炎之分類...............10
(三) 退化性關節炎之診斷方法.............11
(四) 退化性關節炎之原因及致病機轉..........12
(五) 退化性關節炎之治療方法.............23
三、 抗氧化.....................29
(一) 抗氧化基因Nrf2................30
(二) 酵素型抗氧化物................31
(三) 非酵素型抗氧化物...............32


四、 礦物元素硒..................33
(一) 礦物元素硒之生理功能.............34
(二) 硒蛋白....................35
(三) 礦物元素硒與退化性關節炎之相關性.......37
五、 碘醋酸鈉誘導退化性關節炎之動物模式......38
肆、 研究目的.....................39
伍、 實驗材料.....................40
第一部分:細胞實驗(In vitro).................40
一、 細胞株.....................40
二、 細胞實驗藥品與材料...............40
第二部分:動物實驗(In vivo).................48
一、 動物......................48
二、 動物實驗用藥品與材料..............48
第三部分:儀器與設備...................51
陸、 實驗方法.....................53
第一部分:細胞實驗(In vitro).................53
一、 細胞培養(Cell culture)..............53
二、 藥品配製....................55
三、 細胞毒殺試驗..................55
四、 軟骨細胞外基質染色..............56
五、 活性氧化物質(ROS)含量分析...........57
六、 即時定量聚合酶連鎖反應.............57
七、 西方點墨法...................61
八、 麩胱甘肽(Glutathione, GSH)含量分析........64
第二部分:動物實驗(In vivo).................66
一、 建立退化性關節炎動物模式............66
二、 病理組織切片觀察及染色.............69
三、 Wistar大鼠血清之檢測..............69
柒、 實驗結果.....................72
第一部分:細胞實驗(In vitro).................72
一、 碘醋酸鈉(MIA)對人類軟骨瘤細胞株SW-1353之毒殺
能力 .....................72
二、 礦物元素硒(Se)對人類軟骨瘤細胞株SW1353抵抗碘
醋酸鈉(MIA)傷害之影響.............72
三、 碘醋酸鈉(MIA)與礦物元素硒(Se)單獨或合併使用對人
類軟骨瘤細胞株SW1353軟骨基質成分之影響....73




四、 碘醋酸鈉(MIA)與礦物元素硒(Se)單獨或合併使用對
人類軟骨瘤細胞株SW1353基質蛋白質分解酶及軟骨
基質成分基因表現之影響.............74
五、 碘醋酸鈉(MIA)與礦物元素硒(Se)單獨或合併使用對
人類軟骨瘤細胞株SW1353細胞激素(cytokines)相關
基因表現之影響.................75
六、 碘醋酸鈉(MIA)與礦物元素硒(Se)單獨或合併使用對
人類軟骨瘤細胞株SW1353抗氧化能力之影響....77
七、 碘醋酸鈉(MIA)與礦物元素硒(Se)單獨或合併使用對
抗氧化基因Nrf2蛋白質表現之影響.........79
八、 麩胱甘肽(GSH)和超氧化物歧化酶(SOD)對於礦物元
素硒(Se)保護人類軟骨瘤細胞株SW1353之影響...80
九、 碘醋酸鈉(MIA)與礦物元素硒(Se)單獨或合併使用對
麩胱甘肽(GSH)合成酵素基因表現之影響......81
十、 麩胱甘肽(GSH)抑制人類軟骨瘤細胞株SW1353細胞
激素(cytokines)相關基因表現之影響........83
十一、 抗氧化基因Nrf2上游調控因子對於礦物元素硒
保護人類軟骨瘤細胞之SW1353之影響.....84

第二部分:動物實驗(In vivo)................88
一、 退化性關節炎病理組織切片觀察.........88
二、 Wistar大鼠血清中抗氧化物質含量檢測......89
三、 Wistar大鼠血清中細胞激素含量檢測.......90
四、 Wistar大鼠血清中軟骨基質生成蛋白含量檢測....90
捌、 討論.......................92
玖、 參考文獻.....................99
壹拾、 圖表.......................121
壹拾壹、 附錄.....................157
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