臺灣博碩士論文加值系統

骨質疏鬆是一種生理疾病，特徵為低骨量以及骨組織結構退化，導致骨骼脆化，增加骨折的風險。骨質疏鬆症的發病率隨著年齡的增加，尤其好發於絕經後婦女，因為雌激素的缺乏，使停經後婦女蝕骨作用大於成骨作用。在所有預防和治療骨質疏鬆症的方案中，增加鈣的攝取量是最常被推薦的預防措施。克弗爾發酵產物是由酵母菌與乳酸菌共同發酵的乳製品，被認為具有免疫調節、降血壓、促進鈣質吸收、抗微生物等益生功能，在前人研究也指出發酵乳製品對於去卵巢動物模式及老化動物模式具有骨保護的作用，然而克弗爾相關研究付諸闕如，故本研究的目的在評估實驗室自行開發的克弗爾發酵產物對於骨保護功能的效益。實驗分為細胞與動物實驗兩部分，首先我們利用人類大腸癌細胞株Caco-2細胞建立一個模擬腸道鈣離子吸收的細胞模式，經由鈣離子探針Fluo-3與細胞內鈣離子結合產生的螢光值變化可以評估克弗爾發酵產物添加之後對腸道細胞鈣離子吸收的影響。另外利用動物實驗評估克弗爾對於去卵巢大鼠模式延緩骨質流失之功效，將56隻16週齡SD(Sprague-Dawley)大鼠分為7個處理組：假手術組、控制組、克弗爾發酵產物組依人體建議劑量換算後之1倍、2倍及4倍、福善美組(alendronate)、市售產品組 (Rebone)以手術摘除卵巢後，經兩週恢復期以管餵方式進行試驗12週，犧牲後採血液進行骨生化指標分析鹼性磷酸酶(ALP)與C端第一型膠原蛋白胜肽(CTX)。大鼠股骨以甲醛固定後，股骨骨佔組織比例 (BV/TV)、骨小樑厚薄度 (Tb.Th) 、骨小樑數量 (Tb.N)、骨小樑分離度 (Tb.Sp)及緻密骨骨礦物密度 (BMD)與3D重組圖形以高解析度X光電腦斷層掃描儀(Micro-CT)進行分析、配合組織染色切片(H&E stain)觀察骨小樑微結構變化，同時股骨幹以奈米壓痕測試儀(Nanoindention)進行生物力學分析。細胞實驗結果顯示克弗爾發酵產物能夠促進caco-2腸道細胞的鈣離子吸收。此外動物試驗顯示克弗爾發酵產物組可降低去卵巢大鼠骨吸收指標CTX，具有較高的骨礦物質密度並且有效延緩去卵巢導致的股骨部位骨佔組織比例、骨小樑厚薄度、骨小樑數量流失同時降低骨小樑分離率，組織染色切片與Micro-CT重組圖形顯示克弗爾發酵產物處理組有較多的骨小樑分布，生物力學測試測試反應了骨小樑結構的變化，克弗爾發酵產物維持去卵巢大鼠的彈性模數與表面硬度，因此有較高的抗破壞係數。研究結果顯示，克弗爾發酵產物具有開發為預防骨質疏鬆保健產品之潛力。

Osteoporosis is a disease characterized by low bone mass and structural deterioration of bone tissue, leading to bone embrittle and increase fractures risk .The incidence of osteoporosis increases with age and occurs most frequently in postmenopausal women due to estrogen deficiency, as the balance between bone resorption and bone-formation shifts towards increased levels of bone-resorption. among various preventions and cures for osteoporosis .An increase in calcium intake is the most commonly recommended preventive. kefir product is a kind of fermented dairy products made with kefir grains. Fermentation of milk causes degradation of milk proteins into various peptides with health-promoting effects including immunomodulating, antithromobotic calcium-absorption enhancing, and antimicrobial bioactivities. In previous study, the effects of these fermented milk products were benefits on bone metabolism in growing and aged rat models. The aim of this study is to investigate kefir’s effect on osteo-protection. Experiments were divided into two part. Firstly, we using Caco-2 in vitro cell model to assess the effects of kefir product on the calcium uptake, the changes in cytosolic calcium concentration before and after kefir addition analyzed by a fluorometric system using fluo-3 as the Ca2+-sensing probe. Secondly, fifty-six 16-week-old female Sprague-Dawley rats were divided into 7 groups: Sham (normal), Ovariectomized rats (OVX; negative control), OVX rats treated with kefir product of graded doses (dose translation from human to rat, 1X, 2X and 4X, kefir body weight/day), Alendronate 2.5 (OVX/ALN), Rebone (OVX/Rebone) 800 mg/kg body weight per day for 12 weeks. Sham group were treated with phosphate buffered saline. Serum alkaline phosphatase (ALP) and C-terminal telopeptide of type I collagen (CTX) were assessed as the bone turnover markers. Trabecular bone mineral density (BMD) and bone volume (BV/TV), trabecular thickness degree (Tb. Th), trabecular number (Tb.N), trabecular separation (Tb. Sp. ) were determined from distal femurs using a desktop μ-CT system. The mechanical properties (hardness and modulus) of the distal femur were calculated from nanoindentation. Our results showed that kefir product could increase human intestine-like Caco-2 cell calcium uptake. Biochemical markers showed that kefir product treatment groups reduced resorption marker CTX versus OVX group (p < 0.05). Micro-CT data showed that kefir product treatment groups had higher trabecular bone volume/tissue volume (BV/TV) and bone mineral density (BMD) versus OVX group (p < 0.05). Biomechanical data also showed that kefir treatment groups maintained bone stiffness, and hence resistance against breaking. In conclusion, kefir treatment increased calcium uptake in human intestine-like Caco-2 cell model. Oral administration of kefir product in ovariectomized rats could significantly decreased levels of bone turnover markers and prevent ovariectomy-induced bone loss, deterioration of trabecular microarchitecture, and biomechanical reduction .

中文摘要................................................ I
英文摘要................................................ II
目錄..................................................... IV
圖次.................................................... V表次..................................................... IX
附錄.................................................... X

壹、緒論................................................ 1
貳、文獻回顧............................................ 2
一、骨骼與鈣質........................................ 2
(一)鈣質的恆定................................. 2
(二)鈣質的吸收................................. 2
二、骨骼的組成結構、生合成以及代謝..................... 5
(一)骨骼生理構造............................... 5
(二)骨骼的成分與組成........................... 7
(1)成骨細胞 (Osteoblast)........................7
(2)蝕骨細胞（Osteoclast).....................7
(3)骨細胞(Osteocytes)..........8
(三)骨質再塑作用(Bone remodeling) .............................. 8
二、骨質疏鬆症(osteoporosis) ........................ 11
(一)骨質疏鬆症類型................................. 11
(1)、原發性骨質疏鬆症................................ 11
(2)、續發性骨質疏鬆症................................ 11
(二)骨質疏鬆的危險因子............................ 13
(三)骨質疏鬆症之診斷.............................. 13
(四)骨質疏鬆症之治療................................ 16
(1)雌激素補充療法(Estrogen therapy；ET)............... 16
(2)選擇性雌激素受器調節劑(Selective estrogen receptor...
modulators；SERM)........................ 16
(3)副甲狀腺素(Parathyroid hormone；PTH)............ 16
(4)降鈣素(calcitonin；CT )........................ 17
(5)雙磷酸鹽藥物(Bisphosphonates；BPs)............... 17
(6)單株抗體療法............................... 18
三、骨密度與生物力學分析儀器........................... 23
(一)電腦斷層掃瞄儀(computed tomography；CT)........... 23
(二) 奈米壓痕NID測試儀............................... 23
四、細胞鈣離子吸收模式............................... 24
五、骨質疏鬆症動物模式.................................. 25
六、發酵乳於骨質保健之功效與應用........................ 25
七、研究動機與策略.................................... 26
參、材料方法.......................................... 28
一、利用Caco-2細胞進行促鈣吸收實驗................... 29
(一)Caco-2細胞來源..................................... 31
(二)Caco-2細胞繼代培養................................ 31
(三)實驗藥品配置..................................... 31
(四)細胞實驗原理.................................... 31
(五)Caco-2細胞模式螢光值之測定......................... 31
(六)添加鈣離子通道抑制劑對於Caco-2細胞螢光測定值之影響... 32
(1)L型鈣離子通道抑制劑硝苯地平(nifedipine)之處理......... 32
(2)鈣池調控的鈣離子通道抑制劑釘紅(ruthenium red；RuR)之處理.32
(七) 添加內質網鈣離子幫浦抑制劑、鈣離子通道抑制劑後，對於細胞內螢光值測定之影響.........32
(1)添加內質網鈣離子幫浦抑制劑、L型鈣離子通道抑制劑之處理. 33(2)添加內質網鈣離子幫浦抑制劑、TRPV6鈣離子通道抑制劑之處 理.................................... 33
二、摘除卵巢大鼠動物模式管餵克弗爾發酵產物延緩骨質流失功能性評估 35
(一)實驗動物飼養................................ 35
(二)動物模式建立........................................ 35
(三)動物實驗設計與分組............................. 35
(四)管餵藥品的製備.............................. 36
(五)血液生化數值測定.............................. 36
(六)電腦斷層與生物力學測試股骨試片處理................ 36
(七)病理切片股骨試片處理........................... 36
三、骨密度與生物力學儀器之測定流程................ 39
(一)高解析度微型 X光電腦斷層掃瞄儀 (Micro-CT) ....... 39
(1)分析流程....39
(2)參數設定.................................. 39
(3)3D重組操作........................................ 40
(4)骨小樑計算方式.................................. 40
(5)骨礦物質密度BMD計算方式............................... 40
(二)Hysitron奈米壓痕測試儀............................. 41
(1)試片鑲埋.......................................... 41
(2)試片研磨拋光...................................... 41
四、統計方法
肆、結果.......................................... 48
一、細胞實驗結果.................................... 48
(一)克弗爾發酵產物於caco-2細胞內鈣離子螢光值之變化.... 48
(二)克弗爾發酵產物於添加鈣離子通道抑制劑後caco-2細胞鈣離子螢光 值變化....................................... 49
(1)添加L型電感鈣離子通道抑制劑硝苯地平之影響......... 49
(2)添加TRPV5/6鈣離子通道抑制劑釘紅(RuR)之影響........... 49
(三)添加內質網鈣離子幫浦抑制劑 (Tg)與L型鈣離子通道抑制劑後之影響................................. 50
(四)添加內質網鈣離子幫浦抑制劑 (Tg)與TRPV5/6鈣離子通道抑制劑RuR之影響.................................. 50
二、動物實驗結果....................................... 59
(一)去卵巢大鼠體重變化................................... 59
(二)子宮重量與形態變化................................... 59
(三)血液生化數值變化................................... 62
(四)大鼠股骨骨垢部位組織病理染色切片..................... 66
(五)以高解析度微型 X光電腦斷層掃瞄儀重組股骨骨垢部位3D立體結構....................................................... 66
(六)微型X光電腦斷層掃瞄儀評估克弗爾發酵產物對於去卵巢大鼠骨垢部位骨小樑參數之影響........................... 70
(1)以Micro-CT分析遠端股骨骨垢部位骨小樑與組織所佔之比例. 70
(2)以Micro-CT分析遠端股骨骨垢部位骨小樑厚薄度........... 70
(3)以Micro-CT分析遠端股骨骨垢部位骨小樑數量............. 70
(4)以Micro-CT分析遠端股骨骨垢部位骨小樑分離率........... 70
(5)以Micro-CT分析遠端股骨骨垢部位骨礦物質密度............ 70
(七)以奈米壓痕測試儀評估餵食克弗爾發酵產物延緩去卵巢大鼠股骨機械性質弱化之功效....................................... 77
(1)以奈米壓痕機械儀評估克弗爾對於彈性模數之影響......... 77
(2)以奈米壓痕機械儀評估克弗爾對於表面硬度之影響.......... 77
伍、討論................................................ 80
一、克弗爾發酵產物於促進腸細胞鈣離子吸收之功能分析....... 80
二、克弗爾發酵產物作用機制.............................. 80
三、克弗爾於摘除卵巢動物模式生理、生化指標分析.......... 81
四、克弗爾發酵產物於大鼠病理組織切片與電腦斷層掃描影響之分析 ................................................82
五、克弗爾發酵產物於骨骼物理強度影響分析................ 83
陸、總結................................................ 85
柒、參考文獻............................................ 86
圖次
圖1、上皮細胞鈣離子傳輸機制示意圖....................... 4
圖2、股骨解剖構造與哈維氏系統............................ 6
圖3、蝕骨細胞發育與細胞內訊號之調控..................... 9
圖4、骨質再塑作用........................................ 10
圖5、OPG與RANKL以及RANK與RANKL之間的作用機制............. 20
圖6、常見之雙磷酸鹽藥物(BPs)與結構...................... 21
圖7、分泌型醣蛋白Sclerostin與DKK1於細胞表面作用與機制.... 22
圖8、以人類大腸癌細胞株caco-2評估克弗爾發酵產物對於腸細胞內鈣離子吸收之實驗設計..................................... 28
圖9、鈣離子探針於細胞內作用原理......................... 30
圖10、去卵巢大鼠模式評估克弗爾延緩骨質流失功效之實驗架構..38
圖11、電腦斷層掃描與奈米壓痕測試分析流程圖................39
圖12、Micro CT 主體透視圖.................................42
圖13、以Dataviewer軟體與CTAn軟體合成三維影像示意圖........43
圖14、大鼠股骨二維影像選取範圍示意圖......................44
圖15、骨礦物質換算示意圖..................................45
圖16、奈米壓痕測試儀照片與運作示意圖......................46
圖17、奈米壓痕試片與分析示意圖............................47
圖18、添加酪蛋白磷酸胜、原料乳粉肽、克弗爾發酵產物於caco-2細胞內螢光值之影響..........................................52
圖19、添加酪蛋白磷酸胜肽、原料乳粉與克弗爾發酵產物於caco-2細胞模式刺激鈣離子內流導致細胞內鈣離子濃度增加之影響....... 53
圖20、克弗爾發酵產物添加於L型電感鈣離子通道抑制劑硝苯地平後，Caco-2細胞內螢光值之影響............................. 54
圖21、克弗爾發酵產物添加於TRPV6鈣離子通道抑制劑釘紅後，對於Caco-2細胞內螢光值之影響..................................55
圖22、克弗爾發酵產物添加於TRPV6抑制劑釘紅後，Caco-2細胞螢光值之變化..................................................56
圖23、克弗爾發酵產物添加於內質網鈣離子幫浦抑制劑Tg與L型鈣離子通道抑制劑後，對於細胞內螢光值之影響....................57
圖24、克弗爾發酵產物添加於內質網鈣離子幫浦抑制劑Tg與TRPV6鈣離子通道抑制劑後，對於細胞內螢光值之影響..................58
圖25、各處理組餵食12週期間體重之變化......................60
圖26、各處理組餵食12週後性腺重量..........................61
圖27、各餵食處理12週後對於去卵巢大鼠骨骼再塑指標鹼性磷酸酶
(ALP)活性影響分析...................................64
圖28、各餵食處理12週後對於去卵巢大鼠骨骼再塑指標第一型膠原蛋白碳端胜肽活性影響分析.................................. 64
圖29、各處理組餵食12週後對於去卵巢大鼠之組織病理切片......67
圖30、各處理組餵食12週後以Micro-CT系統合成縱向切面之3D圖..68
圖31、各處理組餵食12週後以Micro-CT系統合成正視橫切之3D圖..69
圖32、各處理組餵食12週後以Micro-CT軟體計算遠端股骨骨垢部位骨小樑與組織所佔之比例......................................72
圖33、各處理組餵食12週後以Micro-CT分析遠端股骨骨垢部位骨小樑厚薄度.................................................. 73
圖34、各處理組餵食12週後以Micro-CT分析遠端股骨骨垢部位骨小樑數目 74
圖35、各處理組餵食12週後以Micro-CT分析遠端股骨骨垢部位骨小樑分離率.................................... 75
圖36、各處理組餵食12週後以Micro-CT分析遠端股骨骨垢部位骨礦物質密度............................................ 76
圖37、各處理組餵食12週後以奈米壓痕測試儀分析股骨幹部位緻密骨之彈性模數差異.......................................... 78
圖38、各處理組餵食12週後以奈米壓痕測試儀分析股骨幹部位緻密骨之表面硬度數值差異..................................... 79
圖39、克弗爾發酵產物於促進caco-2細胞株內鈣離子吸收之可能路徑....84
表次
表1、世界衛生組織 (WHO) 骨質疏鬆症分級方式.................... 12
表2、骨質疏鬆導致骨折的危險因子................................ 14
表3、骨生化指標參考項目........................................ 16
表4、具有骨保護效果的蛋白與胜肽類.............................. 28
表5、測定caco-2細胞螢光值變化之各處理組與條件............31
表6、添加L型鈣離子通道抑制劑、克弗爾發酵產物之各處理組與
處理條件................................... 33
表7、表7、添加鈣池調控的鈣離子通道抑制劑釘紅、克弗爾發酵產物之各處理組與處理條件.............................33
表8、添加內質網鈣離子幫浦抑制劑、L型鈣離子通道抑制劑以及
克弗爾發酵產物之各處理組與處理條件...................... 34
表9、添加內質網鈣離子通道抑制劑Thapsigargin(Tg)與TRPV6鈣
離子通道抑制劑RuR後，對於細胞內鈣離子螢光值之影響實驗分 組...................................................... 34
表10、高解析度電腦斷層掃描儀參數設定.....................40
表11、去卵巢大鼠經過克弗爾發酵產物，市售產品Rebone及雙磷酸鹽藥物ALN管餵12週後的血液生化數值變化..................... 63
附錄
附件1、5001飼料成分表...........................100
附件2、餵食克弗爾發酵產物、福善美以及市售產物於實驗期間體重變化 101
附件3、肝、脾、腎與子宮重量、每日攝食量.................102
附件4、餵食去卵巢大鼠12週克弗爾發酵產物、福善美以及市售產品之骨質再塑生化數值......................................103
附件5、雌性大鼠骨質疏鬆症組織病理綜合分數評估.....104
附件6、餵食去卵巢大鼠12週克弗爾發酵產物、福善美以及市售產品以Micro-CT掃描分析之骨小樑數值與骨礦物質密度.... 105
附件7、去卵巢大鼠遠端股骨緻密股部位之奈米壓痕數值.......106
附圖1、動物劑量轉換至人類建議劑量之公式.................107

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