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研究生:楊牧蓁
研究生(外文):Mu-Chen Yang
論文名稱:評估連接蛋白N端胜肽於顳顎關節炎修復之影響
論文名稱(外文):Link Protein N Terminal Peptide in Temporomandibular Joint Arthritis Repair
指導教授:許明倫許明倫引用關係
指導教授(外文):Ming-Lun Hsu
學位類別:博士
校院名稱:國立陽明大學
系所名稱:牙醫學系
學門:醫藥衛生學門
學類:牙醫學類
論文種類:學術論文
論文出版年:2019
畢業學年度:108
語文別:中文
論文頁數:109
中文關鍵詞:顳顎關節炎連接蛋白N 端胜肽弗氏佐劑核磁共振關節積液
外文關鍵詞:Temporomandibular joint arthritisLink Ncomplete Freund's adjuvantMRIjoint effusion
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背景:顳顎關節障礙症(Temporomandibular joint disorder, TMD)為常見之牙科疾病,通常會因疼痛而間接影響關節運動,導致病患生活品質降低。當發炎時期,許多細胞素或蛋白水解酶被誘導出,易造成關節內部硬組織或軟組織受損,進而影響正常功能。由於顳顎關節(Temporomandibular joint, TMJ)軟骨結構主要由纖維軟骨構成,其中具有穩定蛋白聚醣與玻尿酸之間鍵結的連接蛋白(Link protein),會因基質金屬蛋白酶(Matrix metalloproteinases, MMPs)而降解出一段由16 個胺基酸組成的連接蛋白N 端胜肽(Link protein N terminal peptide, Link N)。在同屬於纖維軟骨組織之椎間盤疾病研究顯示,此胜肽片段具有調節發炎和修復組織的功效,但目前顳顎關節炎之動物模式尚未使用連接蛋白N 端胜肽進行治療;此外若此胜肽未來可利用於臨床之治療,勢必先了解病患關節內在不同病變時期之變化,透過核磁共振(Magnetic Resonance Imaging, MRI),以及關節沖洗出之物質來輔助醫師診斷分析。因此本研究之目的:(1)探討連接蛋白N 端胜肽於細胞及大鼠顳顎關節炎動物模式之效益。(2)利用影像學及關節液來評估與分析顳顎關節障礙症。
材料與方法:(1)人類間質幹細胞(Human mesenchymal stem cells, hMSCs)與1ng/mL介白素1β (Interleukin-1β, IL-1β) 、1μg/mL 連接蛋白N 端胜肽(DHLSDNYTLDHDRAIH)共同培養,分別於24 小時及96 小時刺激後收集細胞上清液,以多功能的螢光生物分子多重分析系統分析細胞素的表現,此外收集細胞以觀察24 小時基因的表現。注射50μL 阿爾襄藍染劑(Alcian blue)於大鼠兩側之顳顎關節上關節腔內,以確認注射技術之有效性。分別於第0 天及第7 天注射弗氏佐劑(Complete Freund's Adjuvant, CFA)以誘導大鼠關節發炎後,於第14 天給予0.01mg/μL 連接蛋白N 端胜肽治療,第35 天犧牲後,使用蘇木素-伊紅染色(Hematoxylin and Eosin stain, HE stain)觀察組織型態。(2)27 位顳顎關節障礙症病患以數字疼痛量表(Numeric rating scale, NRS)來評估疼痛程度,並於MRI 拍攝後,依照Wilkes、關節髁頭形變、關節積液之等級分類,再收集病患沖洗出之關節液,使用多功能螢光生物分子多重分析系統來分析關節液內細胞素的表現。
結果:(1)在單獨IL-1β 刺激細胞發炎的環境下,發炎分子IL-6、丙型干擾素誘導蛋白(Interferon gamma-inducible protein, IP-10)、調節活化正常T 細胞表達與分泌趨化因子(Regulated on activation, normal T cell expressed and secreted, RANTES)明顯上升,但在同時有連接蛋白N 端胜肽的環境下,三個分子表現卻明顯下降。相反的,抗發炎分子IL-4、IL-10,以及軟骨分化相關分子如轉化生長因子β1-3 (Transforming growth factor β1-3, TGFβ1-3)和erb-b2 receptor tyrosine kinase 3 (ERBB3)、Nodal homolog (NODAL)基因在共同刺激組與IL-1β 組相比,顯著上升。在CFA 誘導顳顎關節發炎的大鼠模式中,原來變薄的髁頭軟骨(Condylar cartilage, CC)層,在給予連接蛋白N 端胜肽後,有恢復的表現。(2)將27 位顳顎關節障礙症病患之影像進行分析,發現Wilkes 分類與關節髁頭型變有相關性,但與關節積液無相關性。此外關節積液與NRS 有正相關,但與Wilkes 和關節髁頭型變無相關性。相較於關節髁頭型變,關節積液與較多發炎因子IL-8、游離性的介白素6 受器(Soluble IL-6 receptor,
sIL-6R)和抗發炎因子游離性的腫瘤壞死因子受器I/II (Soluble TNF receptor I/II,sTNF-RI/II)有相關性。
結論:在本研究之條件下,在細胞實驗中,連接蛋白N 端胜肽可扮演調節者的角色,幫忙緩解發炎的環境,並增加軟骨相關之分子表現。另外在動物實驗,在給予大鼠顳顎關節炎之治療後,從組織切片可以清楚觀察到關節髁頭的分層有恢復的現象,因此可以初步推測連接蛋白N 端胜肽,具有治療發炎關節的潛力。透過臨床上常見之MRI 影像學分類,關節積液的有無,與較多細胞素表現有相關性,因此可作為顳顎關節障礙症評估的有效指標之一。期望藉由本研究能夠證明出連接蛋白N 端胜肽對於顳顎關節炎之治療潛力,並且透過臨床上更多元的影像學的分類方法,期望能提供牙醫師們在臨床上有更客觀之評估方式。
Background: Temporomandibular joint disorders (TMDs) is a common joint disorder which affecting masticatory actions; it includes joint clicking, joint or muscle pain, and limitations of jaw movement. Under inflammatory conditions, some of cytokines and proteolytic enzymes are induced which may destroy the hard or soft tissue in joint, thereby affecting its function. Due to the cartilage of temporomandibular joint (TMJ) consists of
fibrocartilage, there is a small peptide named Link N which is released from the link protein by matrix metalloproteinase (MMPs). As the same structure of intervertebral disc (IVD), Link N possesses ability to regulate inflammation and joint repair. However, manuscripts are lacking regarding the application of this peptide for TMJ arthritis treatment. If Link N can be used in clinical, we need to realize the change in different pathologic stages. Through the magnetic resonance imaging (MRI) and the cytokine expression in human synovial fluid which may assist clinician for joint diagnosis. Therefore, the aim of this study are: (1) To evaluate the potential of Link N in human mesenchymal stem cells (hMSCs) and in rat TMJ arthritis animal model. (2) To validate the correlation of different MRI grades with cytokine levels of synovial fluid in TMDs patients.
Materials and methods: (1) Cytokines and genes in hMSCs treated with 1μg/mL Link N, 1ng/mL IL-1β, and co-stimulation were undertaken using Luminex multiplex assays and PCR array, respectively. 50μL alcian blue was injected into rat superior TMJ space to confirm the precision of injection skill. At day 0 and day 7, CFA was injected to induce joint inflammation. 0.01mg/μL Link N treatment displayed at day 14. After 35 days following, the tissue morphology was determined by HE stain. (2) 27 patients, who routinely received numeric rating scale (NRS) and MRI assessment before TMJ arthrocentesis, were enrolled. Joint synovial fluid, collected through arthrocentesis were examined for cytokine expression by using a Luminex multiplex assay.
Results: (1) Increased levels of IL-6, IP-10 and RANTES were detected in response to IL-1β treatment, but significantly decreased in the co-stimulation group. In contrast, IL-4, IL-10, TGFβ1-3, ERBB3 and NODAL, were increased significantly in the costimulation group compared to the IL-1β group. Histologic analysis showed significant recovery for rat CC layer in the Link N group when compared to the CFA induced arthritis group. (2) The Wilkes classification was strongly correlated with osseous change scores, but not with joint effusion scores. Joint effusion scores significantly correlated with NRS scores, but not with the Wilkes classification and osseous change scores. Compared with osseous change scores, joint effusion scores had a higher correlation with the levels of inflammatory cytokines (IL-8, sIL-6R) and with anti-inflammatory cytokines (sTNFRI/II).
Discussion: In vivo study, Link N could reduce inflammatory condition and stimulate chondrocyte related factors expression. After injecting Link N in rat TMJ arthritis model, the joint thickness was recovery can be found. Based on these evidence, it could presume that Link N has a potential for arthritis treatment. Through MRI classification, joint effusion scoring showed high correlation with cytokines. It can be a reliable and valid indicator for pathological assessment of TMDs. Results of this study could prove the repair potential of Link N in TMJ arthritis and provide dentist objective evaluation methods through adjective image classification.
中文摘要.................................................i
英文摘要.............................................. iii
目錄 .................................................. v
第一章 緒論 ............................................ 1
第一節 顳顎關節之結構 ................................... 1
第二節 顳顎關節炎 ....................................... 2
第三節 顳顎關節炎之動物模式 .............................. 4
第四節 連接蛋白N 端胜肽之功能 ............................ 7
第五節 連接蛋白N 端胜肽之應用 ............................ 8
第六節 顳顎關節障礙症之影像評估 ......................... 10
第七節 人類顳顎關節液 .................................. 12
第二章 研究設計與目的 .................................. 14
目的一、探討連接蛋白N 端胜肽於細胞及動物實驗之效益 ........ 14
目的二、利用影像學及關節液來評估與分析顳顎關節障礙症 ....... 15
第三章 研究材料與方法 .................................. 16
第一節 連接蛋白N 端胜肽效益之探討 ....................... 16
3.1.1 連接蛋白N 端胜肽製備 ............................. 16
3.1.2 人類間質幹細胞(Human mesenchymal stem cells, hMSCs)收集及培養 .............................................. 16
3.1.3 細胞素之定量 .................................... 16
3.1.4 核糖核酸(RNA)萃取及聚合酶連鎖反應(Polymerase chain reaction, PCR) ....................................... 17
3.1.5 CFA 誘導顳顎關節炎之大鼠動物模式 .................. 17
3.1.6 組織蘇木素-伊紅(Hematoxylin and Eosin, HE)染色及關節髁頭厚度測量 .............................................18
3.1.7 統計方法 ........................................ 18
第二節 利用影像學及關節液來評估與分析顳顎關節障礙症 ....... 18
3.2.1 病患顳顎關節液收集 ............................... 18
3.2.2 關節MRI 影像等級分類 ............................. 19
3.2.3 關節液中細胞素之定量 ............................. 19
3.2.4 統計方法 ........................................ 20
第四章 結果 ........................................... 21
第一節 連接蛋白N 端胜肽效益之探討 ....................... 21
4.1.1 連接蛋白N 端胜肽在發炎的細胞環境下之細胞素分析 ...... 21
4.1.2 連接蛋白N 端胜肽在發炎的細胞環境下之基因變化 ........ 22
4.1.3 探討各組組織切片於不同關節位置之變化 ............... 22
4.1.4 大鼠顳顎關節髁頭厚度及整體組織之變化 ............... 25
第二節 利用影像學及關節液來評估與分析顳顎關節障礙症 ....... 26
4.2.1 病患之關節影像學分類 ............................. 26
4.2.2 關節影像學之相關性分析 ........................... 27
4.2.3 關節影像學與關節液中細胞素之相關性分析 ............. 28
第五章 討論 ........................................... 29
第一節 連接蛋白N 端胜肽效益之探討........................ 29
第二節 利用影像學及關節液來評估與分析顳顎關節障礙症 ....... 33
第六章 結論 ........................................... 37
第七章 圖示、表格說明 .................................. 38
圖示 ................................................. 38
圖示1 大鼠顳顎關節注射技術和解剖相對位置 ................. 38
圖示2 7 天內不同組別之大鼠頭圍及關節解剖變化 ............. 39
圖示3 關節組織切片變化 ................................. 41
圖示4 大鼠顳顎關節組織之基因變化 ........................ 42
圖示5 大鼠顳顎關盤之基因變化 ............................ 43
圖示6 大鼠顳顎髁頭之基因變化 ............................ 44
圖示7 大鼠顳顎關節周邊滑膜組織之基因變化 ................. 45
圖示8 24 小時刺激後發炎相關細胞素之表現 .................. 46
圖示9 24、96 小時刺激後抗發炎相關細胞素之表現 ............ 47
圖示10 96 小時刺激後軟骨相關分子之表現 .................. 48
圖示11 24 小時刺激後上皮細胞間質轉化(Epithelial-mesenchymal transition, EMT)相關基因的表現 ........................ 49
圖示12 大鼠顳顎關節遠心處(Lateral)矢狀切面圖 ............ 51
圖示13 大鼠顳顎關節中間位置(Intermediate)矢狀切面圖....... 53
圖示14 大鼠顳顎關節近心處(Medial)矢狀切面圖 ............. 55
圖示15 大鼠顳顎關節髁頭厚度及整體組織之變化 .............. 58
圖示16 顳顎關節障礙症之病患關節髁頭形變分級 .............. 59
圖示17 顳顎關節障礙症之病患關節積液分級 .................. 60
圖示18 顳顎關節障礙症之病患關節積液像素值分類 ............. 61
圖示19 Wilkes 與髁頭骨形變和關節積液分類之相關性 ......... 62
圖示20 細胞素與不同影像分類方式之相關性 .................. 63
圖示21 細胞素與Wilkes 分類的相關性 ...................... 64
圖示22 細胞素與髁頭骨形變分類的相關性 .................... 65
圖示23 細胞素與關節積液分類的相關性 ..................... 66
圖示24 不同影像學分類及關節液細胞素之簡易說明圖 ........... 67
表格 ................................................. 68
表格1 病患樣本之收集步驟 ............................... 68
表格2 不同組別基因表現之比較 ............................ 69
表格4 顳顎關節障礙症之病患相關資料整理 ................... 70
表格5 EMT PCR array-84 個基因 ......................... 71
第八章 參考文獻 ....................................... 73
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