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系統識別號 U0026-1011201501494900
論文名稱(中文) 單一脈衝電磁場對失用型骨質疏鬆症之治療潛力及機制探討
論文名稱(英文) The therapeutic potentials and mechanism of single-pulsed electromagnetic field on disuse osteoporosis
校院名稱 成功大學
系所名稱(中) 基礎醫學研究所
系所名稱(英) Institute of Basic Medical Sciences
學年度 104
學期 1
出版年 104
研究生(中文) 林摯鈞
研究生(英文) Chih-Chun Lin
學號 S58991293
學位類別 博士
語文別 英文
論文頁數 72頁
口試委員 指導教授-賴國安
召集委員-張南山
口試委員-王國照
口試委員-吳昭良
口試委員-周一鳴
口試委員-安介南
中文關鍵字 單一脈衝電磁場  失用型骨質疏鬆症  坐骨神經切除失用型骨質缺乏小鼠  微型電腦斷層掃描  免疫組織化學染色法 骨母細胞  Wnt  骨形成蛋白2  sclerostin  副甲狀腺類蛋白  DNA微陣列  蝕骨細胞  抗酒酸酸性磷酸酶染色  蝕骨基因  基質金屬蛋白酶9  骨保護素  破骨細胞分化因子 
英文關鍵字 single-pulsed electromagnetic field (SPEMF)  disuse osteoporosis  sciatic denervation disuse osteopenic mice  micro-CT  immunohistochemistric studies  osteoblastic cells  Wnt  BMP2  sclerostin  PTHrP  DNA microarray  osteoclast  TRAP stain  osteoclastic gen 
學科別分類
中文摘要 骨質疏鬆症是目前全球常見的骨科疾病。因疾病如脊髓損傷、中風、肌萎症等所導致的骨骼系統失用則是造成續發性骨質疏鬆之主因之一。單一脈衝電磁場(SPEMF)已知具有促進幹細胞骨分化以及促進小鼠骨質新生之效用。本研究旨在探討單一脈衝電磁場對於失用型骨質疏鬆症之治療潛力及其分子機轉。
小鼠隨機分為四個群組:(1)正常鼠 (2)正常鼠+單一脈衝電磁場 (3)骨質缺乏鼠 (4)骨質缺乏鼠+單一脈衝電磁場。實驗結果顯示,單一脈衝電磁場於治療第六週後便顯著增加骨質缺乏鼠之骨質密度,單一脈衝電磁場治療之骨質缺乏鼠其骨微型參數BV/TV及Tb.N於治療後六週及八週與骨質缺乏鼠相較也顯著增加。此外,治療八週後之骨質缺乏鼠其骨微型參數已與正常鼠無顯著差異。
於骨母細胞中,無論短期或長期單一脈衝電磁場的刺激,皆能促進骨母細胞之礦質化。而鹼性磷酸酶的活性增加則是出現在刺激的前五天內。短期刺激增加了骨化相關基因之表現,如:Wnt1/3a/10b, Fzd9, ALP, 及 Bmp-2。單一脈衝電磁場抑制sclerostin的現象則是出現在刺激五天過後,而此抑制現象在長期刺激中更加顯著。長期單一脈衝電磁場刺激促進了副甲狀腺素相關蛋白的表現,並抑制Sost (sclerostin) 基因的表現。此外,我們進一步利用晶片檢測發現單一脈衝式電磁場刺激亦可活化細胞間隙連接通訊。
於蝕骨細胞中,單一脈衝電磁場並無影響蝕骨基因Acp5, Nfatc1, Ctsk之表現量,僅對Mmp9顯著抑制。此外,單一脈衝電磁場刺激之蝕骨細胞數量與控制組並無顯著差異。
單一脈衝電磁場之刺激增加了骨質缺失鼠之骨質,應可歸因於其對骨母細胞作用促使骨質增生之效應。本研究驗證SPEMF對失用型骨質疏鬆症之治療潛力,期可提供未來臨床之應用。
英文摘要 Osteoporosis is one of the world’s most prevalent bone diseases. Disuse, the lack of skeletal mechanical loading resulting from disease such as spinal cord injury, stroke, or muscular dystrophies, is one of the reasons that leads to secondary osteoporosis. Single-pulsed electromagnetic field (SPEMF) was shown to increase osteogenic differentiation of stem cells, and accelerate new bone formation in mice. Here we investigate the therapeutic potential of SPEMF on disuse osteoporosis, and its underlying molecular mechanism.
Mice were divided into four groups, (1) healthy (INT) mice, (2) INT+SPEMF, (3) denervation-induced osteopenic (IOP) mice, and (4) IOP +SPEMF. The results showed that SPEMF reversed bone loss in IOP mice in 6 weeks. The percent bone volume (BV/TV) and trabecular number (Tb.N) of IOP+SPEMF group were significantly increased than IOP mice on week 6-8. Moreover, the microarchitecture of IOP+SPEMF group was restored to INT levels in 8 weeks.
For osteoblastic cells, both short-term (SS; the first 5 days) and long-term (SL) SPEMF treatment increased the mineralization, while alkaline phosphatase (ALP) activity was increased on the first 5 days of treatment. SS treatment increased gene expression of Wnt1/3a/10b, Fzd9, ALP, and Bmp-2. SPEMF inhibited sclerostin after 5 days of treatment, and that inhibition was more significant by SL treatment. SL SPEMF increased the expression of parathyroid hormone-related protein (PTHrP) but decreased the expression of Sost gene, which encodes sclerostin. Besides, by microarray hybridization, we also found SPEMF-activated gap junctional signaling.
For osteoclastic cells, SPEMF stimulation did not alter the expression of osteoclastic genes, Acp5, Nfatc1, and Ctsk, but down-regulated Mmp9. SPEMF did not significantly decrease the osteoclastic cells.
Together, SPEMF restored bone mass of disuse osteopenic mice, and may contribute to the exert of osteogenesis by osteoblasts. The study validate the therapeutic potential of SPEMF in disuse osteoporosis and provide a new insight for clinical applications.
論文目次 Contents

Abstract IV


Abstract in Chinese V


Acknowledgements VI


Table contents VII


Figure contents VIII


Appendix contents X


Abbreviation list XI


Chapter 1 Introduction 1

1-1 Etiology and prevalence of osteoporosis 1

1-2 Treatment of disuse osteoporosis 3

1-2-1. Treatment of osteoporosis in spinal cord injury 3

1-2-2. Treatment of osteoporosis in stroke 4

1-2-3. Treatment of osteoporosis in muscular dystrophies 5

1-3 The bone environment 5

1-3-1. The structure of bone tissue 5

1-3-2. Osteoblasts and related signalings 6

1-3-3. Osteoclasts and related signalings 7

1-4 Effect of pulsed electromagnetic field on bone diseases 8

1-4-1. In vivo findings of PEMF on bone loss 8

1-4-2. Molecular pathways of PEMF 9

1-5 Effect and therapeutic potential of single pulsed electromagnetic field 10

Chapter 2 Material and methods 12

2-1. The decision of the stimulating parameters of SPEMF 12

2-1-1.Cell culture - osteoblastic cells 12

2-1-2. SPEMF apparatus 12

2-1-3. Alkaline phosphatase activity assay 13

2-1-4. Statistical analysis 13

2-2. SPEMF effect on disuse osteopenic mice 13

2-2-1. Preparations for experimental animals 13

2-2-2. SPEMF apparatus 14

2-2-3. Microarchitecture analysis 14

2-2-4. Statistical analysis 15

2-3. SPEMF effect and mechanism on osteoblastic cells 15

2-3-1. Cell culture - osteoblastic cells 15

2-3-2. SPEMF apparatus 15

2-3-3. Mineralization assay 16

2-3-4. Alkaline phosphatase activity assay 16

2-3-5. Quantitative real-time polymerase chain reaction 17

2-3-6. Immunoblotting 17

2-3-7. Microarray hybridizations and data analysis 18

2-3-8. Statistical analysis 18

2-4. SPEMF effect on osteoclastogenesis 19

2-4-1. Cell culture - osteoclastic cells 19

2-4-2. Cell culture - osteoblastic cells 19

2-4-3. SPEMF apparatus 19

2-4-4. Cell growth assay 20

2-4-5. Tartrate-resistant acid phosphatase Staining 20

2-4-6. Tartrate-resistant acid phosphatase activity assay 20

2-4-7. Quantitative real-time polymerase chain reaction 21

2-4-8. Statistical analysis 21

Chapter 3 Results 22

3-1. The decision of the stimulating parameters of SPEMF 22

3-1-1. For choosing wave forms of SPEMF 22

3-1-2. For choosing stimulation duration of SPEMF 22

3-2. SPEMF effect on disuse osteopenic mice 22

3-2-1. The induction of osteopenia in BALB/C mice 22

3-2-2. The effect of SPEMF in the microarchitecture of IOP mice 22

3-3. SPEMF effect and mechanism on osteoblastic cells 23

3-3-1. Induction of osteoblastic differentiation by SPEMF 23

3-3-2. Upregulation of osteogenic gene expression post SPEMF 23

3-3-3. Effect of SPEMF treatment on sclerostin 24

3-3-4. PTHrP expression was higher and SOST expression was lower after SPEMF 24

3-3-5. SPEMF induced the gap junctional intercellular communication 24

3-4. SPEMF effect on osteoclastogenesis 25

3-4-1. The SPEMF effect on RANKL-induced osteoclastogenesis 25

3-4-2. The expression of osteoclastic genes by SPEMF stimulation 26

Chapter 4 Discussion 27

Tables 32

Figures 38

Appendixes 57

References 60

Curriculum vitae 71
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