創傷性關節炎軟骨之退化進程－ 大鼠模型基因體圖譜研究

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劉志中(Chih-Chung Liu) 查詢紙本館藏

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系統生物與生物資訊研究所

論文名稱

創傷性關節炎軟骨之退化進程－大鼠模型基因體圖譜研究
(Molecular basis of cartilage degeneration in post-traumatic osteoarthritis progression – genome-wide expression study of a rat model)

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摘要(中)

目前針對創傷性關節炎的治療策略為早期介入、延緩病程、保存關節功能、延後置換人工關節的時機。在臨床的情境下，要從病況尚屬早期且症狀輕微的病人身上取得關節軟骨組織進行研究，並不可行。我們利用前十字韌帶截斷與內側半月板切除手術的大鼠模型來進行創傷性關節炎進程的研究，並利用基因體表現圖譜分析來探討創傷性關節炎進程中軟骨退化的分子基礎。在前十字韌帶截斷與內側半月板切除手術前(未手術)、手術後兩周、手術後四周取得軟骨組織，經由組織病理檢查確認軟骨退化隨時間愈趨嚴重。利用主成分分析和階層分群法，將所有軟骨樣本的依照基因表現圖譜來分群，結果發現同時間點的樣本成功地分在同一組群。此外，我們從手術後兩周和四周的軟骨基因表現圖譜分析中，分別篩選出849個以及223個差異表現基因。接下來，我們將手術後兩周與四周的樣本中，上調的差異表現基因，分別進行基因功能註解以及富集分析，得到了15個共同(重複在兩周與四周出現)的生物途徑(biological process)以及1個共同的pathway (ECM-receptor interaction)。利用手術後兩周與四周樣本中，下調的差異表現基因，分別進行基因功能註解以及富集分析，得到了14個共同(重複在兩周與四周出現)的生物途徑(biological process)以及1個共同的KEGG pathway (Axon guidance)。我們更進一步從這些共同生物途徑裡，篩選出重複出現的差異表現基因，找出了40個一致性差異表現基因(consensus differentially expressed genes)。其中22個一致性差異表現基因是新穎基因- 目前並無文獻指出這些基因和關節炎之軟骨退化進程相關。另外，我們的研究也找到了兩個共同KEGG pathway- ECM-receptor interaction and Axon guidance。其中Axon guidance pathway 是一個由兩周和四周皆下調的差異表現基因經富集分析找出的新穎路徑(novel pathway)，其中Sema4d, Plexnb1, Gnai1, Srgap2等四個基因是這個路徑中重複出現在兩周以及四周的一致性差異表現基因。經由免疫組織化學染色來驗證基因圖譜分析的結果，Gnai1蛋白在正常的軟骨組織中有表現，在創傷性關節炎進程中，軟骨內的Gnai1蛋白的表現量持續地下降。我們推測這些axon guidance pathway相關的基因可能和創傷性關節炎進程中的軟骨退化以及疼痛有關。

摘要(英)

Current therapeutic strategy for post-traumatic osteoarthritis (PTOA) is early intervention to attenuate disease progression, preserve joint function, and defer the timing of joint replacement. In clinical scenario, it is impractical to harvest the cartilage samples from the patients with early and mild osteoarthritis. We applied the anterior cruciate ligament transaction and medial meniscectomy (ACLT + MMx) surgery-induced osteoarthritis (OA) model on rats to study the PTOA progression. Genome-wide expression analysis of articular cartilage was performed to explore the molecular basis of cartilage degeneration during PTOA. Articular cartilage was harvested at naïve (time zero), 2 weeks, and 4 weeks after ACLT+MMx surgery. Histopathological examination of articular cartilage revealed that the osteoarthritis progressed in a time-dependent manner. Principal component analysis and hierarchical clustering analysis of gene expression data were performed, and all the samples were divided into three groups and the results were consistent with their time points post-surgery. Furthermore, we identified 849 differentially expressed (DE) genes at 2 weeks, 223 DE genes at 4 weeks after surgery. Gene ontology (GO) enrichment analysis revealed that there were 15 common biological processes as well as one common pathway (hsa04512: ECM-receptor interaction) enriched by up-regulated DE genes at both 2 weeks and 4 weeks post-surgery. 14 common biological processes as well as one common pathway (hsa04360: Axon guidance) were enriched by down-regulated DE genes at both 2 weeks and 4 weeks post-surgery. We further identified 40 consensus differentially expressed genes (cDEGs) from common biological processes enriched at both 2 weeks and 4 weeks post-surgery. 22 of 40 cDEGs were identified as novel genes without currently available evidences regarding the expression on cartilage as well as functioning in osteoarthritis. Moreover, our study suggested that two common pathways were enriched in the progression of PTOA- ECM-receptor interaction and Axon guidance. Axon guidance pathway was a novel pathway enriched by down-regulated DE genes at 2nd and 4th week after surgery, and Sema4d, Plexnb1, Gnai1, Srgap2 were identified as the consensus DEGs within the pathway. Immunohistochemical staining validates the microarray data as Gnai1 protein expressed in normal articular cartilage and persistently decreased during PTOA progression. We speculated that these axon guidance molecules may be involved in cartilage degeneration and pain during PTOA progression.

關鍵字(中)

★ 創傷性關節炎
★ 軟骨退化
★ 基因體圖譜
★ 微陣列

關鍵字(英)

★ post-traumatic osteoarthritis
★ cartilage degeneration
★ genome-wide expression
★ microarray

論文目次

Table of contents
中文摘要................................................ i
Abstract............................................... ii
Table of contents...................................... iii
List for Tables........................................ v
List for Figures....................................... vi
1. Introduction................................... 2
1-1 Osteoarthritis..................................... 2
1-2 Epidemiology....................................... 2
1-3 Risk factors and etiology.......................... 3
1-4 Current treatment options.......................... 4
1-5 Emerging investigational therapeutic agents........ 5
1-6 Genetics of osteoarthritis......................... 5
1-7 Candidate gene study............................... 6
1-8 Genome wide association study...................... 7
1-9 Functional genomics of osteoarthritis.............. 7
1-10 Animal models to study osteoarthritis............. 8
Aim of investigation................................... 10
2. Methods and Materials.......................... 11
2-1 Rat model of posttraumatic osteoarthritis.......... 11
2-2 Histopathological examination of the experimental knee joint.................................................. 11
2-3 RNA extraction and microarray analysis............. 12
2-4 Data analysis processing........................... 12
2-5 Functional enrichment analysis and consensus DEGs identification......................................... 13
2-6 Immunohistochemistry............................... 13
3. Results........................................ 15
3-1 Validation of the rat model of osteoarthritis...... 15
3-2 Gene expression analysis of articular cartilage.... 16
3-3 Functional enrichment analysis..................... 18
4. Discussion..................................... 24
5. Conclusion and Future Directions............... 29
5-1 Summary of study................................... 29
5-2 Directions for future research..................... 30
Reference.............................................. 62

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指導教授

李弘謙(Hoong-Chien Lee)

審核日期

2016-7-28

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