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系統識別號 U0026-1708201616453500
論文名稱(中文) 破骨細胞及其前驅細胞的凋亡機制與抗凋亡策略
論文名稱(英文) The Pro-apoptotic Mechanism and Anti-apoptotic Pathways of Osteoclasts and Osteoclast Precursors
校院名稱 成功大學
系所名稱(中) 生物醫學工程學系
系所名稱(英) Department of BioMedical Engineering
學年度 104
學期 2
出版年 105
研究生(中文) 戴大為
研究生(英文) Ta-Wei Tai
學號 P88001025
學位類別 博士
語文別 英文
論文頁數 89頁
口試委員 指導教授-蘇芳慶
共同指導教授-周一鳴
召集委員-杜元坤
口試委員-林秋烽
口試委員-葉明龍
中文關鍵字 骨質疏鬆  破骨細胞  細胞凋亡  細胞存活 
英文關鍵字 osteoporosis  osteoclast  apoptosis  cell survival 
學科別分類
中文摘要 骨質疏鬆是現今老年人的隱形殺手,所造成的骨折其死亡率約與癌症後期相當。骨質疏鬆在台灣的盛行率相當高,髖部骨折的發生率也是亞洲第一。骨質疏鬆致病機轉主要是體內骨質的製造與流失失去平衡。正常骨內代謝是由骨母細胞(osteoblast)負責生成骨質,而破骨細胞(osteoclast)則負責骨質吸收,一旦這個平衡遭受破壞,就會產生疾病。當破骨細胞的骨吸收作用大於骨母細胞的成骨作用,骨質流失加速,即有可能造成骨質疏鬆。因此現今的治療方式大多著重於幫助骨質生成與抑制骨質流失。雙磷酸鹽類藥物為目前最常見的骨質疏鬆症治療藥物,其作用機轉為直接造成破骨細胞凋亡,可惜治療的結果仍無法令人滿意,因此深入了解破骨細胞的凋亡機制還有治療效果不佳的原因並尋求新的骨質疏鬆治療方式是一個很重要的研究方向。
本研究計劃旨在探討破骨細胞及其前驅細胞的細胞凋亡與存活機制,特定目標一為確認破骨細胞及其前驅細胞的凋亡的訊息傳遞路徑。特定目標二為找出該細胞在雙磷酸鹽類治療下仍能存活的詳細機轉。特定目標三為探討細胞凋亡機制的增強與細胞存活機制的抑制在骨質疏鬆治療的運用。
研究結果顯示當破骨細胞前驅細胞接受雙磷酸鹽類藥物Zoledronic acid刺激後,會造成活性氧化物質以及GSK-3β活化,進而抑制Mcl-1後造成粒線體受損與細胞凋亡。另一方面,某些細胞則透過p38 MAPK啟動保護機制,活化GSK-3β-β-catenin-Bcl-xL訊息傳遞路徑促使細胞存活。在動物實驗中發現,在治療骨質疏鬆的藥物外加p38 MAPK的抑制劑,可以有更好的治療效果。本研究結果除了進一步揭露骨質疏鬆的致病機轉,也可以進一步以此為根據發展預防與治療的方法。
英文摘要 Osteoporosis can cause severe disability. It may increase the risk of death, especially when hip fractures occur. The incidence of osteoporosis and hip fracture is high in Taiwan (the highest in Asia). However, the treatment results for osteoporosis are dismal. Osteoporosis is caused by the imbalance of osteoblasts and osteoclasts. The bone formation of functioning osteoblasts is suppressed, whereas osteoclasts are over activated for bone resorption. Understanding the mechanism of osteoclast apoptosis and the resistance pathways of treatment may help identify new therapeutic targets.
The purpose of this study was to investigate the mechanism of cell apoptosis and the survival of osteoclasts following osteoporosis treatment. The three specific aims are as follows: Specific Aim 1: To understand the mechanism of cell apoptosis in osteoclast precursors and osteoclasts. Specific Aim 2: To understand the mechanism of cell survival in osteoclast precursors and osteoclasts after treatment for osteoporosis. Specific Aim 3: To test the therapeutic effect of enhancing the apoptotic pathway or inhibiting the cell survival pathway.
The results showed that Zoledronic acid-induced apoptosis was mediated by the activation of reactive oxygen species and GSK-3β, followed by Mcl-1 downregulation and mitochondrial damage, resulting in apoptosis. In some cells, the p38 MAPK-mediated pathway was activated to enhance cell survival. This effect was mediated by GSK-3β-β-catenin-Bcl-xL signaling. Furthermore, we found that co-treatment with ZA and a p38 inhibitor might enhance the treatment in an osteoporosis animal model.
We identified the intracellular pro-apoptotic and anti-apoptotic pathways of osteoclast precursors and developed a new treatment strategy. The results contribute to the knowledge of the pathophysiology of osteoporosis and have clinical relevance.
論文目次 Abstract in Chinese I
Abstract in English II
Acknowledgements IV
Abbreviations V
Contents VII
Chapter 1. General Introduction 1
1.1 Introduction to osteoporosis 1
1.1.1 Osteoporosis 1
1.1.2 Epidemiology 2
1.1.3 Pathogenesis 3
1.1.4 Treatment 4
1.2 The Role of ROS in ZA-induced Apoptosis 5
1.3 The Mechanism of Non-response or Resistance to ZA in Osteoporosis Treatment 6
Chapter 2 Objective and Specific Aims 8
2.1 Specific Aim 1 8
2.2 Specific Aim 2 8
Chapter 3 Materials and Methods 10
3.1 Cell Models 10
3.2 Mouse Model of Osteoporosis: Ovariectomy Model 10
3.3 Reagents 11
3.4 Osteoclast Formation Assay 12
3.5 Cell Death Assay 13
3.6 Proliferation Assay 13
3.7 Western Blot Analysis 14
3.8 Immunostaining 14
3.9 Determination of ROS Production 15
3.10 Mitochondrial Functional Assay 15
3.11 Lentiviral-based RNA Interference Transfection 16
3.12 Mcl-1 Overexpression 17
3.13 Real-time RT-PCR 17
3.14 Determination of the Bone Mineral Density 17
3.15 MicroComputed Tomography 18
3.16 Biomechanical Tests 18
3.17 Statistical Analysis 19
Chapter 4 Results 20
4.1 Reactive Oxygen Species Are Required for Zoledronic Acid-Induced Apoptosis in Osteoclast Precursors and Mature Osteoclasts 20
4.1.1 ZA treatment induces apoptosis in monocytes, macrophages and differentiated osteoclasts. 20
4.1.2 ZA treatment causes caspase activation during the apoptosis of osteoclast precursors. 22
4.1.3 ROS mediates the apoptotic pathway in ZA-stimulated osteoclast precursors. 24
4.1.4 MAPKs cannot promote the apoptosis of osteoclast precursors. 27
4.1.5 Overexpression of Mcl-1 promotes cell survival. 29
4.1.6 GSK-3β activation is required for ZA-induced Mcl-1 downregulation and cell apoptosis. 31
4.1.7 Treatment of ZA induces a loss in the mitochondrial transmembrane potential. 33
4.1.8 A hypothetic model of cell apoptosis induced by ZA. 35
4.2 Activation of p38 MAPK-regulated Bcl-xL Signaling Increases Survival against Zoledronic Acid-induced Apoptosis in Osteoclast Precursors 36
4.2.1 ZA inhibits cell growth (accompanied by cell death) and survival in osteoclast precursors. 36
4.2.2 Inducible Bcl-xL mediates the cell survival response in ZA-treated osteoclast precursors. 38
4.2.3 Activation of p38 MAPK positively regulates Bcl-xL expression and cell survival in ZA-treated osteoclast precursors. 40
4.2.4 The activation of β-catenin by p38 MAPK mediates Bcl-xL expression and cell survival in ZA-treated osteoclast precursors. 42
4.2.5 p38 MAPK regulates the inactivation of GSK-3β in ZA-treated osteoclast precursors. 44
4.2.6 Inhibiting p38 MAPK facilitates ZA-induced apoptosis and inhibition of RANKL-induced differentiation in osteoclasts. 46
4.2.7 SB203580 enhances the ZA treatment effect on increasing the bone density in osteoporotic mice. 47
4.2.8 SB203580 enhances the ZA treatment effect on increasing bone volume in osteoporotic mice. 49
4.2.9 SB203580 ZA treatment together with SB203580 increases bone strength in osteoporotic mice. 52
Chapter 5 Discussion 54
5.1 The mechanism of apoptosis via ZA in osteoporosis. 54
5.2 ROS play an important role in the cell death pathway. 55
5.3 Understanding the ZA treatment for osteoporosis and developing a new therapeutic strategy. 57
5.4 The mechanism of resistance to ZA in osteoporosis. 57
5.5 p38 MAPK plays an important role in the cell survival pathway. 59
5.6 The search for advanced combination therapy to treat osteoporosis. 60
5.7 Limitations 62
Chapter 6 Conclusion and Future Work 63
References 67
Figures
Figure 1. Proposal for the in vivo study 11
Figure 2. Micro CT 18
Figure 3. ZA treatment induces apoptosis in monocytes, macrophages, and differentiated osteoclasts. 21
Figure 4. ZA treatment causes caspase-3 activation. 23
Figure 5. ZA treatment triggers ROS generation followed by ROS-mediated cell apoptosis. 25
Figure 6. MAPK activation is not involved in ZA-induced cell apoptosis. 28
Figure 7. ZA treatment downregulates Mcl-1 expression by ROS to promote cell apoptosis. 30
Figure 8. GSK-3β is regulated by ZA-induced Mcl-1 downregulation and cell apoptosis. 32
Figure 9. Inhibiting ROS and knockdown of GSK-3β decrease the ZA-induced loss of the MTP in RAW264.7 cells. 34
Figure 10. A hypothetic model of ZA-induced cell apoptosis. 35
Figure 11. ZA inhibits cell growth, followed by either cell death or survival. 37
Figure 12. Inducible Bcl-xL mediates cell survival after ZA treatment. 39
Figure 13. Activation of p38 MAPK by ZA regulates Bcl-xL expression and cell survival. 41
Figure 14. ZA causes p38 MAPK-regulated β-catenin-mediated Bcl-xL expression and cell survival. 43
Figure 15. ZA causes p38 MAPK-regulated inactivation of GSK-3β. 45
Figure 16. Inhibiting p38 MAPK facilitates ZA-induced apoptosis and inhibition of RANKL-induced osteoclast differentiation and enhances ZA treatment of osteoporosis in ovariectomized mice. 48
Figure 17. Inhibiting p38 MAPK enhances the ZA treatment of osteoporosis and increases the bone volume in the proximal tibial metaphysis of ovariectomized mice. 50
Figure 18. ZA treatment of osteoporosis with inhibition of p38 MAPK shows a trend of increased bone volume in the distal femoral metaphysis of ovariectomized mice. 51
Figure 19. ZA treatment of osteoporosis with inhibiting p38 MAPK shows a trend of increased bone strength in the vertebral bodies of ovariectomized mice. 53
Figure 20. Diagram of a hypothetical model of the intracellular apoptotic and survival pathways in osteoclast precursors after ZA treatment. 64
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