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博碩士論文 etd-0213108-000403 詳細資訊
Title page for etd-0213108-000403
論文名稱
Title
Dexamethasone與Pioglitazone引導骨髓間質細胞脂肪化的機轉:成骨細胞分化及骨質疏鬆機轉的研究
The mechanism of Dexamethasone- and Pioglitazone-Induced Adipogenesis in Bone Marrow Stromal Cell: studies on the differentiation of osteoblast and the mechanism of osteoporosis
系所名稱
Department
畢業學年期
Year, semester
語文別
Language
學位類別
Degree
頁數
Number of pages
91
研究生
Author
指導教授
Advisor
召集委員
Convenor
口試委員
Advisory Committee
口試日期
Date of Exam
2007-07-30
繳交日期
Date of Submission
2008-02-13
關鍵字
Keywords
Dexamethasone、骨質疏鬆、Pioglitazone、骨髓間質細胞、脂肪化、成骨細胞
osteoblast, Bone Marrow Stromal Cell, Adipogenesis, Pioglitazone, Dexamethasone, osteoporosis
統計
Statistics
本論文已被瀏覽 5663 次,被下載 1731
The thesis/dissertation has been browsed 5663 times, has been downloaded 1731 times.
中文摘要
骨質疏鬆定義為骨骼質量降低及細微構造損傷的骨骼疾病,會造成骨骼容易碎裂,增加骨折發生的危險。隨著年齡的增加,骨髓的脂肪細胞也隨之增加。在組織學研究骨質疏鬆時發現,骨質疏鬆的患者,其骨髓內脂肪細胞的量與大小均增加。不論造成骨質疏鬆的原因為何,這種脂肪組織取代骨髓正常細胞的現象是骨質疏鬆的共同病理表現。骨髓腔內未分化的間葉細胞可以分化成肌肉細胞、骨母細胞、軟骨細胞及脂肪細胞。任何引起間葉細胞分化的不平衡使脂肪細胞過多或骨母細胞不足,都可能造成骨質疏鬆的病態。已知長期使用類皮質糖會造成骨質疏鬆,其組織學變化亦呈現骨髓脂肪化的現象。以小鼠骨髓間葉細胞株D1作研究發現,正常條件下會分化成骨母細胞的細胞在類皮質糖的誘導下會分化為脂肪細胞。
骨髓間葉細胞分化為骨母細胞或脂肪細胞是受某些轉錄因子的控制(如RUNX2 及PPARγ)。轉錄因子誘導骨髓細胞脂肪化一定有其重要的角色。PPARγ與葡萄糖與脂質的代謝有緊密的關係。因此類皮質糖的誘導D1分化成脂肪細胞可能是經由PPARγ路逕。Tiazolidinedione (TZD)為一種常用於治療糖尿病的降血糖藥物,是PPARγ受體的刺激劑,過去很少報導其與骨骼代謝的關係。本研究顯示,Pioglitazone(一種常用於治療糖尿病的TZD)和類皮質糖一樣,可誘導原本會分化成骨母細胞間葉細胞株D1分化成脂肪細胞。
由於TZD和類皮質糖的主要作用都須透過與細胞核受體的結合,TZD和類皮質糖可能分別經由PPARγ和類皮質糖受體的活化誘導脂肪生成。有趣的是,PPARγ和類皮質糖受體的拮抗物BADGE及RU486均不能抑制脂肪的生成。以PPARγ和類皮質糖核受體結合的進一步分析發現,D1細胞對PPARγ和類皮質糖沒有反應,PPARγ和類皮質糖引起的脂肪生成不是經由PPARγ和類皮質糖的核受體路逕。
結果顯示PPARγ和類皮質糖引起的脂肪生成是經由多路徑的細胞訊息傳導。以基因微陣列分析發現,類皮質糖的確會誘導許多脂肪生成相關基因的表現。
研究顯示類皮質糖引起骨質疏鬆的機轉,部分是經由誘導骨髓間葉細胞脂肪化所造成。另外,現今常用的治療糖尿病的藥物—TZD也會引起骨髓間葉細胞脂肪化,在使用TZD這一類的藥物時,須留意可能引發骨質代謝問題的副作用。
Abstract
Osteoporosis is defined as a skeletal disorder characterized by low bone mass and microarchitectural deterioration of bone tissue, leading to enhanced bone fragility and a consequent increase in fracture risk. Osteoporosis is well known increasing with age. The number and size of marrow adipocytes increase in a linear manner with age. Early histomorphometric observations suggested that the consequence of the adipose replacement of the marrow functional cell population was a cause of osteoporosis. The replacement of functional cells in the marrow by fat cells is common in several pathological study of osteoporosis. All these evidences clearly demonstrate the reciprocal relationship between osteoblast and adipocyte differentiation. The trans-differentiation of osteoblast to adipocyte is an important mechanism of pathogenesis of osteoporosis. Several reports have indicated that the long-term use of steroids could induce osteonecrosis and osteoporosis. Using a mouse pluripotent mesenchymal cell, D1, as a model, we have demonstrated that dexamethasone, a glucocorticoid, can induce adipogenesis.

Peroxisome proliferator-activated receptors-γ (PPARγ) plays a critical role in glucose and lipid metabolism, macrophage function, and adipogenesis. It is a nuclear hormone receptor, activated through ligand binding, which results in allosteric changes in receptor conformation, recruitment of coactivators, assembly of a transcriptional complex, there regulates gene expression. Thiazolidinedione (TZD) is one of the agonist of PPARγ receptor which has been a medication for diabetic mellitus for years. Treatment with TZDs leads to selective accumulation of subcutaneous adipose tissue. We examined whether adipogenesis induction in D1 cells is initiated by activation of peroxisome proliferator-activated receptor-γ. The results revealed that pioglitazone induces adipogenesis in D1 cells in dosedependent manner and decreases alkaline phosphatase activity in D1 cells.

Interestingly, this adipogenesis was not blocked by bisphenol A diglycidyl ether, a peroxisome proliferator-activated receptor-γ antagonist. A peroxisome proliferator-activated receptor-γ-mediated reporter gene assay showed no response to pioglitazone. We then asked whether dexamethasone-induced adipogenesis can be repressed by mifepristone (RU486), an antagonist of glucocorticoid receptor. The results disclosed that mifepristone cannot counteract dexamethasone-induced adipogenesis, and mifepristone itself induced adipogenesis in D1 cells. Moreover, glucocorticoid receptor-mediated reporter gene assay was not responsive to dexamethasone or mifepristone. We concluded that the adipogenesis induced by pioglitazone and dexamethasone in D1 cells may not occur via a peroxisome proliferator-activated receptor-γ and glucocorticoid receptor pathway.

These results suggested that the adipogenesis induced by glucocorticoids and pioglitazone is directed by a multiple cell signaling pathway. Finally, data from microarray analysis confirmed this adipogenesis pathway, as several adipogenesis-related genes are highly provoked by DEX. We found that the expressions of several adipogenesis-related genes are highly provoked by this agent.

Our studies suggest that the adipocyte conversion of bone marrow stromal cells may be the mechanism of bone loss caused by pioglitazone. Considering its widespread clinical use, the detrimental skeletal effects of pioglitazone should be closely monitored.
目次 Table of Contents
謝誌………………………………………………….…………………………..……………..i
摘要………………………………………………..……………………………………..……ii
Abstract……………………………………………………………………………………….iv
Table of Contents…………………………………………………………………………….vii
List of Tables………………………………………………………………………...............viii
List of Figures………………………………………………………………………...............ix
Chapter 1 Background…………………………………………………………………………1
Chapter 2 A Cell Model of Glucocorticoid-Induced Adipogenesis…………………………..12
Chapter 3 Pioglitazone Induces D1 Cell Adipogenesis………………………..……………..18
Chapter 4 GR & PPARγ Pathways in Glucocorticord-Induced Adipogenesis……………….25
Chapter 5 Expressed Gene Profile of Glucocorticoid-Induced Adipogenesis……………….33
Chapter 6 Conclusion………………………………………………………………………...38
References……………………………………………………………………………………41
Tables & Figures………..…………………………………………...……………………….48
Appendix………………………………………………………………………………..……69
Appendix A. Glucocorticoids and Bone Disorders……………………..…………………69
Appendix B. Publications………………………………………………………………….77
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