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研究生:簡言軒
研究生(外文):Yen-Hsuan Jean
論文名稱:興奮性胺基酸在大鼠膝部早期退化性關節炎之角色
論文名稱(外文):The role of excitatory amino acids in early osteoarthritis of knee joint in rats
指導教授:汪志雄汪志雄引用關係
指導教授(外文):Chih-Shung Wong
學位類別:博士
校院名稱:國防醫學院
系所名稱:醫學科學研究所
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:2006
畢業學年度:94
語文別:中文
論文頁數:98
中文關鍵詞: 退化性關節炎 膝部 興奮性胺基酸 麩胺酸 前十字韌帶 發炎
外文關鍵詞:osteoarthritiskneeexcitatory amino acidsglutamateanterior cruciate ligamentinflammation
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退化性骨關節炎是一種最常見的關節疾病,約佔美國人口中年紀大於七十五歲者之80%。近年來在歐美工業高發展國家,因此疾病所需花費之經費估計約佔其國民總生產毛額之1-2.5%。在台灣因嚴重退化性骨關節炎也同美國般所費不眥,每年健保需給付新臺幣約120億元來治療嚴重的退化性關節炎疾病。退化性關節炎是多數致病因所產生,通常是由關節區域之軟骨組織發生病變所致。臨床上主以關節疼痛及關節活動受限表現。傳統上退化性骨關節炎被認為是一非發炎性的疾病,但在一些研究卻發現關節液中有許多發炎性的因子參與其中。
本論文之研究目的有二:(一)、利用動物(大鼠)接受前十字韌帶切除後建立早期退化性關節炎動物模式,並利用膝關節腔微透析之方法探討興奮性胺基酸在早期退化關節炎所扮演之角色。(二)、建立早期退化性關節炎動物模式第8週後以玻尿酸(hyaluronic acid, HA)和cyclooxygenase-2 (COX-2)抑制劑parecoxib進行關節腔內注射,來探討上述兩藥物對於早期退化關節炎之進展影響及關節透析液中興奮性胺基酸濃度之改變情形,期找出早期關節炎之分子細胞學之相關機轉及其治療與預防途徑。
本研究第一部份主要以三個月大之雄性Wistar大鼠(體重約為275-320公克重)為材料,以氣體isoflurane麻醉進行手術右或左膝之前十字韌帶動物模式。接受前十字韌帶切除或Sham手術組乃採隨機分配。在手術20週後,可誘發膝部早期之退化性關節炎,再利用關節腔內微透析技術,收集來自每隻大鼠的雙側膝部關節之透析液。同時利用高效液相層析儀方法測定透析液中各胺基酸之濃度,探討關節腔內興奮性胺基酸在退化性骨關節炎中所扮演之角色。於完成透析液收集後犧牲大鼠,取其膝部關節之軟骨及滑膜,以組織染色實驗(Hematoxylin/eosin和Safranin-O染色)來檢定其退化關節炎之情形。研究之第二部份是於大鼠接受前十字韌帶切除手術第8週後,以1 mg玻尿酸和100 μg parecoxib進行每週一次,連續五週之關節腔內注射,待手術20週後,評估兩者治療退化性關節炎之效果及測定關節腔中興奮性胺基酸濃度之改變情形。
研究結果發現在前十字韌帶切除之膝部退化性關節炎之組別,其關節透析液中興奮性胺基酸麩胺酸(glutamate)、天門冬酸(aspartate)之濃度顯著高於對側sham組,而其它種類之胺基酸如serine, glutamine, glycine, arginine, citrulline及taurine在兩組間則無顯著之差異。而在玻尿酸和parecoxib之治療結果中發現此兩藥物不但可以顯著延緩膝部股骨內髁軟骨退化的嚴重度及改善了滑膜炎,也可同時降低治療組其關節透析液中興奮性胺基酸(麩胺酸、天門冬酸)之濃度。
本論文研究經文獻查證得知為首件以微透方析法來測定動物早期退化關節炎之關節液中興奮性胺基酸濃度之動物實驗研究。雖然人類之退化性關節炎是多數致病因所產生的,我們希望能以此動物早期退化關節炎模式為基礎,應用興奮性胺基酸在疼痛及發炎所扮演的角色與本研究之重要發現,提供退化性關節炎或其他關節疾病(如類風濕性關節炎)另一種治療之參考。未來的研究將續應用早期退化關節炎動物模式,進行興奮性胺基酸如麩胺酸及其協同劑,拮抗劑如ketamine、MK-801和dextromethorphan等藥物之關節腔內注射之實驗。另以西方墨點試驗來驗證動物膝部退化性關節炎組織(軟骨、半月板及滑膜)與麩胺酸相關代謝途徑之蛋白質表現,期提供臨床研究者新觀念及後續關節炎相關疾病之新知。
Osteoarthritis (OA) is the most common joint disorder in the world, it is presented, with radiographic evidence, in 80% of people over the age of 75 in USA. The cost of the illness has risen up to 1-2.5% of the gross national product of many industrialized countries in recent decades. The economic impact of OA is enormous in the USA as well as in Taiwan. In Taiwan, around 12 billion NT was paid every year for advanced stage of OA. OA is a multifactorial degenerative joint disease in which the cartilaginous matrix of the articular joint is destroyed. The clinical manifestations are pain and restricted motion, although the disease is classified as a noninflammatory arthropathy, several inflammatory components have also been observed in the synovial fluid during the disease process.
The aims of this research including two. The first is to investigate the role of excitatory amino acids (EAAs) in early OA of rat knee joint were set up after anterior cruciate ligament transection (ACLT). Secondly, the effects of intra-articular injection of hyaluronic acid (HA) and cyclooxygenase-2 (COX-2) inhibitor parecoxib on the development of early OA and the concomitant changes in EAA levels in dialysates of ACLT knee joints were examined. Hopefully, the cellular mechanisms and biological changes associated with OA will offer new treatment strategies to prevent the progression of OA.
The first part of this study is to establish the OA model. Wistar rats, weighing between 275 and 320 gm were used. Transection of anterior cruciate ligament (ACL) was performed under isoflurane anesthesia. The knee for the ACLT or sham-operated was randomly assigned. After surgery, rats were set for weight bearing for 20 weeks to induce early OA. Microdialysis sampling was obtained from the injured as well as the contralateral joints. The dialysates were examined for EAAs by high performance liquid chromatography (HPLC). Animals were sacrificied and the histology of the knees were examined with hematoxylin/eosin (H/E) and Safranin-O staining. The second part of this study is to examine the effect of intra-articular injection of HA and COX-2 inhibitor parecoxib on the early OA development. Either HA (1mg) or parecoxib (100μg) was injected intra-articularly in the ACLT knee once a week for 5 consecutive weeks starting at the 8th week after surgery. Twenty weeks after surgery, knee joint dialysates were collected by microdialysis and EAA levels was assayed by HPLC, the histopathology was examined to correlate the concomitant changes of EAA levels in dialysates of ACLT knee joints.
Our results demonstrated that early OA of knee joint was observed in rats at 20 weeks after ACLT. The concentration of glutamate and aspartate in the dialysates of ACLT knee were increased significantly than that of the contralateral sham-operated joint, while other amino acids (such as serine, glutamine, glycine, arginine, citrulline and taurine) were not different. Rats received HA and parecoxib treatment showed a significant lower degree of cartilage degeneration on the medial femoral condyle at both the macroscopic level and on the Mankin grading scale than rats receiving saline. Both intra-articular HA and parecoxib injection suppressed the synovial inflammation. Moreover, EAA glutamate and aspartate levels were reduced by HA and parecoxib treatment compared to the saline control group in ACLT knee joint dialysates.
To our knowledge, by using microdialysis technique, this is the first study on the biochemical profiles of EAAs in early OA animal model. Although the multiple etiologies of human OA, in this early OA animal model, an increase of glutamate and aspartate concentrations in the OA joint dialysates was found in our study. We believe, by adding the knowledge of EAAs in the pain and inflammation, it will offer another way of therapy of OA, and other arthritis such as rheumatoid arthritis (RA). It worths further research, by using microdialysis technique, to evaluate the effect of intra-articular injection of glutamate, glutamate antagonists such as ketamine, MK-801 and dextromethorphan on the OA joint. Protein expression of knee tissues (cartilage, meniscus and synovia) associated with glutamate metabolism will also be examined. We believe, these novel findings will provide a valuable stategy for the treatment of OA.
目錄
正文目錄 ……………………………………………………… II
表目錄…………………………………………………………. IV
圖目錄 ………………………………………………………... V
英文縮寫……………………………………………………… VII
附錄目錄……………………………………………………… IX
中文摘要……………………………………………………… X
英文摘要……………………………………………………… XII





















正文目錄
第壹章、序論 ………………………………………………… 1
第一節、退化性關節炎…………………………………… 1
第二節、興奮型胺基酸(Excitatory Amino Acids, EAAs). 2
第貳章、實驗材料與方法……………………………………… 11
第一節、動物模式之建立 (Animal Model)……………… 11
第二節、膝部微透析管製作及微透析………………….. 12
第三節、膝關節透析液內胺基酸含量的測量………….. 17
第四節、動物犧牲後膝關節組織之病理切片檢驗……… 21
第五節、數據分析……………………………………….. 24
第參章、以微透析法探討前十字韌帶切除之大鼠膝部關節液中興奮性胺基酸濃度之變化………………………… 25
第一節、實驗模式之背景……………………………….. 25
第二節、實驗步驟………………………………………… 27
第三節、實驗結果………………………………………… 27
第四節、討論……………………………………………… 37
第五節、後記…………………………………………….... 39
第肆章、探討關節內注射玻尿酸(Hyaluronic acid)在大鼠前十字韌帶切除產生之退化性關節炎和其關節透析液中興奮性胺基酸之角色………………………………
40
第一節、材料和方法.…………………………………….. 42

第二節、結果……………………………………………. 45
第三節、討論………………………………. ……………. 56
第四節、後記…………………………………………….. 60
第伍章、探討關節內注射Cyclooxygenase-2抑制劑在大鼠前十字韌帶切除產生之退化性關節炎和其關節透析液中興奮性胺基酸之角色………………. …………….
61
第一節、材料及方法……….. …………. ………………. 64
第二節、結果…………………………………………….. 67
第三節、討論………………………………. ……………. 77
第四節、後記……………………………….. ……………. 82
第陸章、結論與展望…………………………………………… 83
參考文獻………………………………………………………... 87
附錄…………………………………………. …………………. 98














表目錄
表3-1 在顯微鏡下評估關節軟骨退化的程度……………….. 31
表3-2 在顯微鏡下評估滑膜炎的程度……………………….. 32
表4-1 大鼠股骨內髁關節軟骨的肉眼觀察評估…………….. 50
表4-2 股骨內髁及滑膜組織之組織病理學評估…………….. 51
表5-1 大鼠股骨內髁關節軟骨的肉眼觀察評估…………….. 71
表5-2 股骨內髁軟骨及滑膜組織之組織病理學評估……….. 72






















圖目錄
圖1-1 研究架構……………………………………………….. 9
圖2-1 大鼠膝關節微透析示意圖……………………………… 14
圖2-2 動物微透析管置入圖…………………………………… 15
圖2-3 自製微透析管結構圖…………………………………… 16
圖2-4 收集naïve大鼠關節透析液達3小時,測量其雙側興奮性胺基酸中麩胺酸及天門冬酸,雙側皆呈現穩定……………………………………………………….. 19
圖2-5 本研究初期以naïve大鼠以HPLC可分析測得多種胺基酸……………………………………………………. 20
圖2-6以naïve大鼠膝關節組織切片染色…………………… 23
圖3-1 大鼠經前十字韌帶切除後,隨時間的變化,其膝關節寬度增加情形………………………………………….. 30
圖3-2 顯微鏡下膝關節組織病理切片結果………………….. 33
圖3-3 顯微鏡下膝關節組織病理切片結果,大鼠手術後20週之滑膜組織病理切片(H/E染色,×200) …………… 34
圖3-4 大鼠手術後20週後關節透析液興奮性胺基酸(麩胺酸及天門冬酸)濃度改變圖………………………………. 35
圖3-5 大鼠手術後20週後關節透析液其它胺基酸濃度的測定………………………………………………………... 36
圖4-1 實驗設計………………………………………………… 44
圖4-2 大鼠接受手術後20週,大鼠經前十字韌帶切除後,隨時間的變化,其膝關節寬度增加情形……………… 49
圖4-3 大鼠股骨內髁軟骨和滑膜之組織病理切片評估……… 52
圖4-4 ACLT之膝關節以玻尿酸和食鹽水治療組的關節透析液中,興奮性胺基酸濃度測定結果……………… 54
圖5-1 實驗設計………………………………………………. 66
圖5-2 大鼠經前十字韌帶切除後,隨時間的變化,其膝關節寬度增加情形…………………………………………. 73
圖5-3 大鼠股骨內髁軟骨和滑膜之組織病理評估…………. 74
圖5-4 ACLT後之膝關節以parecoxib和食鹽水治療組的關節透析液中,興奮性胺基酸濃度測定結果………… 76
圖6-1 ACLT引發之膝部退化性關節炎動物模式中EAA之細胞內訊息傳遞機轉…………………………………. 86























英文縮寫
ACL anterior cruciate ligament
ACLT anterior cruciate ligament transection
Asp aspartate
CNS central nervous system
COX cyclooxygenase
EAAs excitatory amino acids
EAAC-1 excitatory amino acid carrier-1
GDH glutamate dehydrogenase
GLAST glutamate/aspartate transporter
GS glutamaine synthetase
Gln Glutamine
Glu glutamate
GLT-1 glutamate transporter-1
iGluR ionotropic glutamate receptor
mGluR metabotropic glutamate receptor
HA hyaluronic acid
HPLC high performance liquid chromatography
i.a intra-articular
ICAM-1 intercellular adhesion molecular-1
IL-1β interleukin-1 beta
IL-1R interleukin-1 receptor
i.p intra-peritoneal


i.v intra-veous
i.m intra-muscular
MK-801 dizocilpine
NF-κB nuclear factor-kappa B
NMDA N-methyl-D-aspartate
NO nitric oxide
OA osteoarthritis
PGs prostaglandins
PVDF polyvinylidene difluoride
RA rheumatoid arthritis
RT-PCR reverse transcription-polymerase chain reaction
TNF-α tumor necrosis factor-alpha
VGLUT1 vescicular glutamate transporter isoenzyme-1
VGLUT2 vescicular glutamate transporter isoenzyme-2



















附錄目錄
附錄一、刊登於 Journal of Orthopedic Research 的論文
附錄二、已接受刊登於 Journal of Orthopedic Research 的接受函及論文
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