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研究生:葉青華
研究生(外文):Ching-Hua Yeh
論文名稱:醣皮質固醇與酒精引起之骨質壞死症機制之研究
論文名稱(外文):The studies of the mechanism of glucocorticoid and alcohol induced osteonecrosis
指導教授:王國照
指導教授(外文):Gwo-Jaw Wang
學位類別:博士
校院名稱:高雄醫學大學
系所名稱:醫學研究所
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:2008
畢業學年度:97
語文別:中文
論文頁數:95
中文關鍵詞:骨質壞死症骨髓間葉幹細胞酒精醣皮質固醇
外文關鍵詞:Osteonecrosishuman bone marrow mesenchymal stem cellalcoholGlucocorticoiddexamethasonelovastatinWnt
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中文摘要:

骨質壞死症(Ostenecrosis;ON) 是骨細胞受到直接或間接的危險因子而導致細胞死亡的結果。長期服用醣皮質固醇 (Glucocorticoid, GC)、酗酒、抽煙、高血脂症以及高黏稠性血症等危險因子皆會誘發骨質壞死症。其中以長期服用醣皮質固醇所誘發的ON與飲酒所誘發ON最為常見。醣皮質固醇與酒精(Alcohol, Alc)造成ON的機制到目前為止仍未清楚。本論文主要研究為研究醣皮質固醇與酒精誘發骨壞死症的致病機轉。
本研究分成兩階段以及兩個部份:第一階段探討ON與非ON (Non-ON)病人的骨髓間葉幹細胞(HBMSCs),其骨質生成與脂肪新生基因的表現及其骨質分化及脂肪分化的能力是否有異,探討基因表現以釐清引起ON的原因。第二階段的研究包含兩個步驟,第一個部份是研究ON與Non-ON病人的骨髓幹細胞HBMSC 以醣皮質固醇(Dexamethasone ;Dex) 及降血脂藥物(Lovastatin ;Lov)處理過後的骨質生成相關基因表現。第二個部份的研究在於探討酒精誘發ON的機制是否透過Wnt/β-catenin 訊息傳遞作用產生。首先,以 10個長期服用醣皮質固醇誘發ON(GC-induce ON)病人的HBMSCs以及10個因酗酒誘發ON(Alc-ON)病人的HBMSCs作為實驗組(ON group);而10個退化性關節炎(osteoarthritis;OA) 病人及股骨骨折(Trauma;TA)病人的HBMSCs為對照組(Non-ON group)進行研究。分析病人的骨質生成基因及脂肪生成基因的表現,其次分析Dex與 Lov處理的HBMSCs骨質生成基因的表現,最後用分子生物學的研究方式分析醣皮質固醇與酒精造成的骨質壞死症的機制。
第一階段的結果顯示,脂肪生成基因方面 (如PPAR???n及 adipsin),在ON 組較Non-ON 組表現為高,特別是Alc-ON組相較於GC-induce ON組其脂質生成基因的表現顯示有意義的上升。相反的, ON 組相較於Non-ON group組在osteocalcin、BMP2、Runx2、osteonectin和osteopontin等等骨質生成基因的表現顯示顯著性的下降,而ON 組別中GC-induced ON組的基因的下降量相較於Alc-ON組更為有意義的下降。
從ON病人分離的HBMSCs脂肪生成基因的表現量較Non-ON組為高。而脂肪新生基因在GC-induced ON組的HBMSCs的表現更高於Alc-ON組以及Non-ON 組。然而,GC¬-induced ON組的骨質生成基因的表現量較其它兩組的來得少。在第一階段組織學的研究方面,兩個ON組在礦物化的分析方面,Alizarin red S的表現量自第七天以後明顯的比Non-ON組低;而GC-induced ON在地11天以後的表現量比酒精誘發的ON又更低;相反的,在脂肪新生的分析方面,Oil red O (脂滴)的表現量在第三天後,ON組相較於Non-ON組為高,而酒精誘發的 ON的表現量也比GC-induced ON產量高。Alizarin red S stain 與Oil red O的結果顯示,ON病人HBMSCs較不易礦物化但較容易分化成脂肪細胞。
第二階段第一部份的的研究指出Dex 抑制ON 與Non-ON BMP2跟Osteocalin的基因表現,並且抑制的能力在ON組是比較強的,相反的,Lov提高兩種基因的表現量並且可以回復Dex在所有HBMSCs所造成的基因表現的抑制現象。更進一步的,ON 組BMP2 表現量的抑制較Non-ON組為多,然而在Lov所造的回復現象相較於Alc-ON,GC誘發的ON其BMP2的回復量是比較少的。細胞經由Dex處理後Osteocalcin基因的表現量都是下降的,但是Lov 的回復作用在兩組ON都是不好的。我們相信個體對藥物的感受性不同,當其接受到Dex與Lov的刺激之後可能造成基因表現量的不同。這可能可以解釋為何有些人服用GC會導致ON有些人則不會。
第二階段第二部份的結果顯示,酒精降低Wnt/β-catenin 訊息傳遞下游骨質生成標靶基因Runx2, osteocalcin 以及 BMP2的表現,此外酒精增加Wnt/β-catenin 訊息傳遞下游脂肪生成標靶基因PPARγ的表現量;然而,酒精抑制Wnt/β-catenin 訊息傳遞因子LRP5, Wnt3a and β-catenin的表現,相反的酒精促進 Wnt/β-catenin 訊息傳遞拮抗因子SFRP2 and DKK1的表現量增加。在免疫螢光組織化學的研究方面,酒精抑制β-catenin 從細胞質轉移到細胞核使Wnt/β-catenin 訊息傳遞進行的的能力。在蛋白質的層面,酒精抑制β-catenin 表現量與酒精濃度改變呈現負相關現象,增加PPARγ的表現量,則與酒精濃度的改變有正相關性。但是Dex誘發細胞的SFRP1基因表現量上升,酒精處理細胞則觀察到SFRP2基因的表現量上升,但LRP5以及DKK等等的基因表現量在兩種藥物處理後表現量一致。
綜合以上三個研究,觀察到個體基因的表現上的差異與ON形成有正相關。關於醣皮質固醇以及酒精所誘發的ON機制研究上,醣皮質固醇以及酒精可能經由抑制Wnt/β-catenin 訊息傳遞造成骨髓幹細胞系統性的功能不良,將導致脂肪細胞的堆積於病灶區,而導致骨質壞死症狀的形成。
ABSTRACT

Osteonecrosis (ON) is a pathologic process resulting from direct or indirect injury to the osteoblast. Long-term treatment of glucocorticoid (GC), alcoholism, smoking, hyperlipidemia and hyperviscosity are high risk factors leading to ON. The mechanism of GC- and alcohol-induced ON is still unknown. Therefore, the purpose of this research was to investigate the pathogenesis of ON induced by glucocorticoid and alcohol in human.
This experiment research was divided into two phases: phase I was to identify the gene expression profile and the differentiation ability of isolated HBMSCs from patients with and without ON; phase II included two stages to (1) investigate the effect of dexamethasone (Dex, 0.1 µmol/L) and/or lovastatin (Lov,1 µmol/L) on osteogenic gene expressions in HBMSCs from patients with and without ON, and (2) investigate the role of Wnt/β-catenin signaling pathway in alcohol induced ON. Firstly human bone marrow stroma cells (HBMSCs) were isolated from 10 patients with alcohol-induced ON and 10 patients with GC-induced ON as well as 10 patients (osteoarthritis or trauma) without ON (both ON groups were experimental groups, non-ON patients as control group), and then the osteogenic and adipogenic differentiation ability were analyzed. Secondly, the effect of Dex and Lov on the isolated HBMSC was evaluated through the osteognic ability. Finally, the mechanism of GC- and alcohol- induced ON was investigated by molecular cell biology.
The results of phase I study show that PPAR?? and adipsin of adipogenesis genes of both ON groups are significantly higher than those form non-ON group, especially the PPAR?? and adipsin of alc-induced ON group are also significantly higher than GC-induced ON group; on the contrary, Type I collage, BMP2, Runx2, osteonectin and osteopontin of osteogenesis genes from both ON groups are significantly lower than those from non-ON group, especially the osteogenic genes of GC-induced ON group are also significantly lower than those from Alc-induced ON group. The HBMSCs from patients with ON have more adipogenic gene expressions than non-ON group. The HBMSCs from GC-induced ON patients have more adipogenic gene expressions compared to Alc-induced ON and non-ON groups. However, the osteogenic genes from GC-induced ON group are more down-regulated than other two groups. The results of histology analysis in phase I show that the amount of Alizarin red S of both ON groups are less than that of non-ON group after 7th day later, and the amount of GC-induced ON is less than that of alc-induced ON after 11th day later. On the contrary, the amount of Oil red O are higher in ON groups compared to non-ON group after 3rd day later, and even higher in alc-induced ON group compared to GC-induced ON group after 3rd day later. The findings of phase I experiment indicate that the HBMSCs isolated from patients with ON have less mineralization but more adipogenesis ability.

The results of quantitative real time PCR analysis in stage I of phase II indicate that Dex suppress BMP2 and osteocalcin gene expressions on ON and non-ON groups, and the suppressive effect of Dex is more obvious on ON groups than non-ON patients; on the contrary, Lov can enhance these gene expressions and reverse the inhibition effect of Dex on all groups. The BMP2 mRNA expression of both ON groups are more suppressed by Dex compared to non-ON group, but the effect of lovastatin on reversing the inhibition effect of Dex is less enhanced on the GC-induced ON group. The osteocalcin mRNA expression of both ON groups are also more suppressed by Dex compared to non-ON group, but the effect of lovastatin on reversing the inhibition effect of Dex are less enhanced on both ON groups. The findings demonstrate that patients with GC-induced ON are seem to more susceptible to Dex-induced suppression of BMP2 and osteocalcin expressions than patients with alcohol-induced ON. It is believed that different susceptibility of drug on individuals might change the gene expression when encountered by Dex and Lov. This might explain how drug -induced ON could be dependent on different individuals.
The results of stage II in phase II show that alcohol decreases the down stream target genes, Runx2, osteocalcin and BMP2 of osteogenic genes, but increases PPARγ of adipogenic gene; however, alcohol decreases LRP5, Wnt3a and β-catenin of the Wnt/β-catenin specific genes, but up-regulate the antagonist SFRP2 and the inhibitor DKK1 of Wnt /β-catenin signal pathway. The results of immune-fluorescence analysis indicate nuclear translocation of β-catenin is hampered by alcohol, in which the inhibition of β-catenin protein is negatively proportional to alcohol concentration but the up-regulation of PPAR?? protein is positively correlated with alcohol concentration. The expressions of LRP5 and DKK1 for Des treated cells are similar to those of alcohol treated cells, but Dex promotes gene expression of SFRP1 yet alcohol increases gene expression of SFRP2. The experimental investigation indicates that ethanol decreases osteogenesis and increases adipogenesis through the Wnt/β-catenin signaling pathway in human BMSCs, also decreases nuclear translocation of β-catenin to reduce bone specific gene expressions. The findings agree to previous scientific researches that the Wnt signaling pathway has involved in the regulation of homeostasis of bone mass.

In conclusion, the gene expressions of each individual can be identified to be associated with ON. In the mechanism of GC and alcohol induced ON, hampering Wnt/β-catenin signal pathway may cause systemic dysfunction on HBMSCs, which may lead to fat accumulation and progressive to osteonecrosis.
CONTENTS

ABSTRACT…………………………………………………………… 1
中文摘要………………………………………………………… 2
致謝.. ……………………………………………………………… 6
CONTENTS………………………………………………………… 12
LIST OF TABLE……………………………………………………. 15
LIST OF FIGURE…………………………………………………. 16
CHAPTER 1 INTRODUCTION……………...………………… 19
1.1 History and Epidemiology of ON………...……… 20
1.2 Classification and the Candidate Sites of ON …… 21
1.3 The Risk Factors of ON...………………...……..… 21
1.4 The Pathogenic Change of ON.. .………………...… 22
1.5 Previous Animal Studies of ON………………...… 23
1.6 Human Bone marrow mesenchymal stromal cells (HBMSCs) …………...………………...…………… 24
1.7 The Mechanism of steoblastogenesis………...… 26
1.8 Growth Factors and Transcription Factors………. 27
1.9 The Mechanism Studies of ON…...…………… 29
1.10 Purpose and Specific Aims…...…………… 32
Research Hypothesis…...………...………… 33
Significance... ………...………………….…… 33
CHAPTER 2 MATERIALS AND METHODS…………….…… 34
2.1 The History of Cases……………….…...…………… 36
2.1.1 Phase I and Stage 1of Phase II….…...…………… 36
2.1.2 Stage 2 of Phase I……………….…...…………… 37
2.2 Isolation Human Bone Marrow Mesenchymal Stromal Cells (HBMSCs) ….…...………………. 38
2.3 Primary Cell Culture ………….…...…………… 39
2.4 Differentiation (Osteogenesis and Adipogenesis): 40
2.4.1 Osteogenesis and Alizarin Red S Stain: ………….… 40
2.4.2 Adipogenesis and Oil Red O Stain: ………….… 41
2.5 Data Analysis and Statistics: ………….… 43
2.5.1 Data Analysis of Phase I : ………….… 43
2.5.2 Data Analysis of Stage 1 of Phase II………….… 43
2.5.3 Data Analysis of Stage 2 of Phase II………….… 44
2.6 RNA Extraction and RT-PCR Analysis ………….… 44
2.6.1 Quantitative Real-time PCR (q-PCR) and Primers 45
2.7 Alkaline Phosphates Activity Analysis………….… 46
2.8 Protein Analysis by Western Blots………….… 46
2.9 Immunofluorescence Analysis at Stage 2 of Phase II 49
2.10 Drugs Treatment………….……………. 50
2.10.1 Drugs Treatment at Stage 1of Phase II………….… 50
2.10.2 Drugs Treatment at Stage 2 of Phase II………….… 51
CHAPTER 3 RESULTS………….…………….…………… 52
3.1 Phase I results: Characteristics of Isolated HBMSCs From Patients With and Without ON 52
3.1.1 Osteogenic and Adipogenic Gene Expressions 52
3.1.2 Alkaline Phosphase Analysis………….… 54
3.1.3 Mineralization Analysis………….… 56
3.1.4 Adipogenesis Analysis………….… 58
3.2 Stage 1 of Phase II: Test The Osteogenic Gene Expressions in HBMSCs from Patients With and Without ON after Dex and LovastatinTreatment 61
3.2.1 The Results of BMP2 and Osteocalcin Gene expressions by RT-PCR: ………….…………….… 61
3.2.2 The Results of BMP2 and Osteocalcin Gene expressions by RT-PCR and Quantitative Real-Time PCR………….…………….……………. 62
3.3 Stage 2 of Phase II: Examine the mechanism of alcohol induced ON by Wnt/β-catenin signaling pathway………….…………….…………….……… 70
3.3.1 Gene expressions………….…………….…………… 70
3.3.3 Immunohistochemistry………….…………….… 75
CHAPTER 4 DISCUSSION………….…………….…………….… 77
4.1 Discussions of Phase I………….…………….… 77
4.2 Discussions of Stage I of Phase II………….… 79
4.3 Discussions of Stage 2 of Phase II : ………….… 82
CHAPTER 5 CONCLUSIONS and RECOMMENDATION 86
REFERENCE 87
APPENDIX 94
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