本文關(guān)鍵詞：糖尿病對(duì)口腔種植體骨整合影響的作用機(jī)制研究　出處：《山東大學(xué)》2015年博士論文　論文類型：學(xué)位論文

  更多相關(guān)文章： 種植體 骨結(jié)合 高糖 糖尿病 PI3K/AKT 整合素 纖維粘連蛋白

【摘要】：背景和目的：口腔種植是治療缺牙患者的最有效途徑。B ranemark在1971提出的“骨結(jié)合Osseointegration"概念成為種植體成功的最重要標(biāo)準(zhǔn)。穩(wěn)定的骨結(jié)合依賴于成骨細(xì)胞在種植體表面的粘附和增殖分化,這一過程受到多種局部和全身因素的影響。糖尿病作為口腔種植治療的相對(duì)禁忌癥,一直受到學(xué)者們的關(guān)注,被公認(rèn)為是影響種植體骨結(jié)合的最重要系統(tǒng)因素之一。本研究擬從體外實(shí)驗(yàn)觀察高糖對(duì)MC3T3-E1細(xì)胞增殖、成骨分化的影響,并分析PI3K/Akt信號(hào)通路在其中的調(diào)節(jié)作用機(jī)制；從體內(nèi)實(shí)驗(yàn),通過糖尿病大鼠模型,檢測(cè)不同血糖水平大鼠種植體周圍骨組織變化及整合素α5β1和纖維粘連蛋白(FN)表達(dá)水平,綜合評(píng)價(jià)糖尿病對(duì)種植體骨結(jié)合影響的作用機(jī)制。材料與方法：體外實(shí)驗(yàn)：PI3K/AKT通路對(duì)不同高糖狀態(tài)下MC3T3-E1細(xì)胞成骨分化的影響根據(jù)文獻(xiàn)選取四種培養(yǎng)基糖濃度：5.5mmol/L,15.5mmol/L,25.5mmol/L, 35.5mmol/L,分別模擬人體內(nèi)正常生理糖濃度及不同程度高血糖濃度,并根據(jù)是否添加PI3K/AKT通路抑制劑LY294002來(lái)分為八組：1)5.5mM糖濃度組(5.5mM-)；2)15.5mM糖濃度組(15.5mM-);3)25.5mM糖濃度組(25.5mM-);4)35.5mM糖濃度組(35.5mM-);5)5.5mM糖濃度+LY294002組(5.5mM+);6)1 5.5mM糖濃度+LY294002組(15.5mM+);7)25.5mM糖濃度+LY294002組(25.5mM+);8)35.5mM糖濃度+LY294002組(35.5mM+)；其中,5.5mM糖濃度組(5.5mM)為對(duì)照組。甲基噻唑基四唑(MTT)法測(cè)定1d,3d的細(xì)胞增殖；堿性磷酸酶(ALP)活性檢測(cè)3d,7d的細(xì)胞分化情況；茜素紅染色觀察7d,14d細(xì)胞分泌鈣結(jié)節(jié)的情況；熒光實(shí)時(shí)定量PCR測(cè)定Run mRNA和OCN mRNA基因分別在3d、7d的表達(dá)；蛋白免疫印跡(Western blot)檢測(cè)3d、7d磷酸化蛋白激酶(p—Akt)的表達(dá)。體內(nèi)實(shí)驗(yàn)：糖尿病大鼠種植體周圍骨結(jié)合的機(jī)制研究33只3月齡雄性健康ZDF(Zucker diabetic fatty)大鼠隨機(jī)分為3組,每組11只,每只大鼠植入2顆種植體。A組：對(duì)照組,ZDF大鼠皮下注射等量生理鹽水,直接植入種植體(11只大鼠,22顆種植體)；B組：ZDF大鼠接受艾塞那肽緩釋納米球治療(皮下注射,0.74%,0.1m]/100g),并同時(shí)植入種植體(11只大鼠,22顆種植體)；C組：ZDF大鼠接受艾塞那肽緩釋納米球治療(皮下注射,0.74%,0.1ml/100g),至血清葡萄糖維持在恒定水平(≤16mmol/L),然后植入種植體(11只大鼠,22顆種植體)。種植手術(shù)后,在第7d、14d、30d、60d分批次處死大鼠,外科手術(shù)取出雙側(cè)股骨,去凈肌肉、粘膜等軟組織,隨后使用切割鉆切取種植體近遠(yuǎn)中3mm的范圍的骨塊,從而得到一個(gè)包含種植體的長(zhǎng)方形骨塊標(biāo)本(第7d,標(biāo)本數(shù)n＝4個(gè)/每組,第14d、30d、60d,標(biāo)本數(shù)分別為n=6個(gè)/每組)。通過硬組織切片、HE染色觀察種植體周圍骨代謝狀況,并通過免疫組化檢測(cè)種植體周圍整合素α5β1和纖維粘連蛋白的表達(dá)。結(jié)果：MTT實(shí)驗(yàn)結(jié)果顯示,在第24h,與對(duì)照組相比,15.5mM-和25.5mM-組的吸光度值均沒有顯著變化(PO.05)；然而,35.5mM-組的吸光度值較對(duì)照組顯著降低,差異具有統(tǒng)計(jì)學(xué)意義(P0.05)；在第72h,與對(duì)照組相比較,15.5mM-組的吸光度值有顯著升高,差異具有統(tǒng)計(jì)學(xué)意義(P0.05)；然而,25.5mM-和35.5mM-組的吸光度值較對(duì)照組顯著降低,且差異具有統(tǒng)計(jì)學(xué)意義(P0.05)。此外,在每一時(shí)間點(diǎn),使用LY294002處理過的四組細(xì)胞的吸光度值較對(duì)照組均顯著下降,差異具有統(tǒng)計(jì)學(xué)意義(P0.05)ALP實(shí)驗(yàn)結(jié)果顯示,在第3d,與對(duì)照組相比較,15.5mM-組、25.5mM-組、35.5mM-組的吸光度值均無(wú)顯著變化,差異沒有統(tǒng)計(jì)學(xué)差異(P0.05),然而,添加LY294002處理的四組細(xì)胞的吸光度值較對(duì)照組均顯著降低,差異具有統(tǒng)計(jì)學(xué)意義(P0.05)；在第7d,15.5mM-組表現(xiàn)出最高的吸光度值,且與對(duì)照組相比具有統(tǒng)計(jì)學(xué)差異(P0.05),然而,25.5mM-組和35.5 mM-組的吸光度值較對(duì)照顯著降低,差異具有統(tǒng)計(jì)學(xué)意義(P0.05)。此外,經(jīng)LY294002處理的四組細(xì)胞的吸光度值較對(duì)照組顯著降低(P0.05),其中,15.5 mM+組的吸光度值高于5.5 mM+組、25.5 mM+組和35.5 mM+組,且差異具有統(tǒng)計(jì)學(xué)差異(P0.05)。茜素紅染色結(jié)果顯示,在第7d,15.5mM-組鈣結(jié)節(jié)的積分吸光度值顯著高于對(duì)照組及其他實(shí)驗(yàn)組,差異具有統(tǒng)計(jì)學(xué)意義(P0.05),同時(shí),25.5mM-組和35.5mM-組鈣結(jié)節(jié)的積分吸光度值也要高于對(duì)照組,且差異具有統(tǒng)計(jì)學(xué)差異(P0.05),此外,經(jīng)LY294002處理的四組細(xì)胞的鈣結(jié)節(jié)積分吸光度值較對(duì)照組均顯著降低,差異具有統(tǒng)計(jì)學(xué)意義(P0.05)；在第14d,與對(duì)照組相比,15.5mM-組鈣結(jié)節(jié)的積分吸光度值要顯著增高,差異具有統(tǒng)計(jì)學(xué)意義(P0.05),然而,25.5mM-組和35.5mM-組鈣結(jié)節(jié)的積分吸光度值與對(duì)照組相比無(wú)顯著差異(P0.05),同樣,經(jīng)LY294002處理的四組細(xì)胞的鈣結(jié)節(jié)積分吸光度值較對(duì)照組均顯著降低,差異具有統(tǒng)計(jì)學(xué)意義(P0.05)。成骨相關(guān)轉(zhuǎn)錄因子(Runt-related transcription factor 2, RunX2)表達(dá)結(jié)果顯示,在第3d,5.5mM+組的基因相對(duì)表達(dá)量顯著低于對(duì)照組,且差異具有統(tǒng)計(jì)學(xué)意義(P0.05),其余各組的基因相對(duì)表達(dá)量與對(duì)照組相比沒有明顯差異(P0.05)；在第7d,15.5mM-組的基因相對(duì)表達(dá)量較對(duì)照組明顯增高,差異具有統(tǒng)計(jì)學(xué)意義(P0.05),同時(shí),15.5mM+組的基因相對(duì)表達(dá)量與對(duì)照組相比無(wú)顯著差異(P0.05),其余各組的基因相對(duì)表達(dá)量均較對(duì)照組顯著降低(P0.05)。鋅指結(jié)構(gòu)轉(zhuǎn)錄因子(Osterix)表達(dá)結(jié)果顯示,在第3d,5.5mM+組的基因相對(duì)表達(dá)量顯著低于對(duì)照組,且差異具有統(tǒng)計(jì)學(xué)意義(P0.05),15.5mM-組的基因相對(duì)表達(dá)量顯著高于對(duì)照組,且差異具有統(tǒng)計(jì)學(xué)意義(P0.05),其余各組的基因相對(duì)表達(dá)量與對(duì)照組相比沒有明顯差異(P0.05)在第7d,15.5mM-組及15.5mM+組的基因相對(duì)表達(dá)量較對(duì)照組均明顯增高,差異具有統(tǒng)計(jì)學(xué)意義(P0.05),同時(shí),5.5mM+組的基因相對(duì)表達(dá)量與對(duì)照組相比明顯降低,且有統(tǒng)計(jì)學(xué)意義(P0.05),其余各組的基因相對(duì)表達(dá)量與對(duì)照組相比沒有明顯差異(P0.05)。骨橋蛋白(Osteoprotegerin, OPN)結(jié)果顯示,在第3d與7d兩個(gè)時(shí)間點(diǎn)各組的變化趨勢(shì)一致,15.5mM-組、25.5mM-組及15.5mM+組的基因相對(duì)表達(dá)量顯著高于照組,且差異具有統(tǒng)計(jì)學(xué)意義(P0.05),35.5mM+組的基因相對(duì)表達(dá)量與對(duì)照組相比顯著降低,且差異具有統(tǒng)計(jì)學(xué)意義(P0.05),其余各組的基因相對(duì)表達(dá)量與對(duì)照組相比沒有明顯差異(P0.05)。骨鈣蛋白(osteocalcin, OCN)結(jié)果顯示,在第3d,15.5mM-組的基因相對(duì)表達(dá)量顯著高于對(duì)照組,且差異具有統(tǒng)計(jì)學(xué)意義(P0.05),5.5mM+組的基因相對(duì)表達(dá)量顯著低于對(duì)照組,且差異具有統(tǒng)計(jì)學(xué)意義(P0.05),其余各組的基因相對(duì)表達(dá)量與對(duì)照組相比沒有明顯差異(P0.05)；在第7d,15.5mM-組、25.5mM-組及25.5mM-組的基因相對(duì)表達(dá)量較對(duì)照組明顯增高,差異具有統(tǒng)計(jì)學(xué)意義(P0.05),同時(shí),5.5mM+組、25.5mM+組及35.5mM+組的的基因相對(duì)表達(dá)量顯著低于對(duì)照組,且差異具有統(tǒng)計(jì)學(xué)意義(P0.05),15.5mM+組的基因相對(duì)表達(dá)量與對(duì)照組相比無(wú)顯著差異(P0.05)。蛋白免疫印跡(Western blot)檢測(cè)P-Akt的表達(dá)結(jié)果顯示,在第3d,15.5mM-組的P-AKT表達(dá)量顯著高于對(duì)照組,且差異具有統(tǒng)計(jì)學(xué)意義(P0.05),25.5mM-組的P-AKT的表達(dá)量較對(duì)照組無(wú)明顯變化(P0.05),其余各組的P-AKT表達(dá)量均較對(duì)照組顯著降低(P0.05)；在第7d,15.5mM-組和25.5mM-組的P-AKT表達(dá)量較對(duì)照組無(wú)顯著差異(P0.05),其余各組的P-AKT表達(dá)量均較對(duì)照組顯著降低(P0.05)。硬組織切片觀察結(jié)果顯示,術(shù)后30天,A組：骨沒有填滿種植體與骨組織之間的空腔；B組：在種植體與骨組織之間的空腔中,填滿了新形成的編織骨,且骨與種植直接接觸,沒有纖維組織細(xì)胞的干擾；C組：和B組相比較,新形成的編織骨更加緊致規(guī)則,種植體表面的骨開始重建并出現(xiàn)類骨質(zhì)沉淀。術(shù)后60天,C組的種植體周圍包繞著非常致密的骨組織,可見骨細(xì)胞沉積在板層骨上,新舊骨組織之間可觀察到結(jié)合線；A組和B組的骨-種植體結(jié)合狀況與C組類似。HE染色結(jié)果顯示：術(shù)后7天：三組均未見明顯的新生骨,并且有大量的炎性細(xì)胞浸潤(rùn)；術(shù)后14天,對(duì)照組和實(shí)驗(yàn)組均未見明顯的新生骨,可見較多活躍的破骨細(xì)胞,C組的炎性細(xì)胞明顯少于A組和B組,且C組的松質(zhì)骨較其他兩組更為致密。A組和B組的破骨細(xì)胞數(shù)目在14天后達(dá)到峰值,C組在第7天達(dá)到峰值,并隨時(shí)間逐漸下降；但C組的平均破骨細(xì)胞數(shù)目較A組、B組沒有顯著差異,p0.05。免疫組化染色觀察種植體周圍整合素α5β1及纖維連接蛋白的表達(dá)結(jié)果顯示,纖維連接蛋白及其受體主要在種植體周圍骨組織中及破骨細(xì)胞表面表達(dá),而整合素α5β1則主要在成骨細(xì)胞表面表達(dá)。纖維連接蛋白及整合素α5β1在C組中的表達(dá)要高于其他兩組。整合素α5β1的光密度值表達(dá)顯示,在整個(gè)實(shí)驗(yàn)過程中,C組種植體周圍骨組織中整合素α5β1的表達(dá)要顯著高于A組和B組(p=0.003)。在第7天,A組和B組的整合素α5β1表達(dá)量相同(p0.05),但是,在第14天,B組的整合素α5β1表達(dá)量要顯著高于A組(p=0.027),第30天以后,A組和B組的差異沒有統(tǒng)計(jì)學(xué)意義(p0.05)。纖維粘連蛋白的光密度值表達(dá)顯示,在整個(gè)實(shí)驗(yàn)過程中,C組種植體周圍骨組織中纖維粘連蛋白的光密度值表達(dá)顯著高于A組和B組(p=0.012)。在第7天、14天、30天,A組和B組的纖維粘連蛋白沒有統(tǒng)計(jì)學(xué)差異(p0.05),但是,在第60天開始,B組的纖維粘連蛋白表達(dá)量要顯著高于A組(p=0.001)。結(jié)論：1.適當(dāng)?shù)母咛?如15.5mM)能促進(jìn)MC3T3-E1細(xì)胞的增殖及成骨分化,過高的糖濃度(25.5 mM和35.5 mM)則起抑制作用；2.P13K/Akt信號(hào)通路在成骨細(xì)胞的增殖、成骨分化等生理過程中起到重要作用；3.血糖濃度得到穩(wěn)定控制的糖尿病大鼠,較對(duì)照組更早的開始成骨代謝,其種植體周圍能形成良好的骨結(jié)合；4.整合素α5 β1及纖維粘連蛋白在種植體-骨結(jié)合過程中起到重要調(diào)節(jié)作用,糖尿病得到良好控制的大鼠表現(xiàn)出更高的整合素α5β1及纖維粘連蛋白的表達(dá)。
[Abstract]:Background and purpose: oral implant is the most effective way to treat the patients with tooth deficiency. The "bone binding Osseointegration" concept proposed by B ranemark in 1971 has become the most important criterion for the success of the implant. A stable bone binding depends on the adhesion and proliferation of osteoblasts on the surface of the implant. This process is affected by a variety of local and systemic factors. Diabetes as a relative contraindication of dental implant therapy has attracted the attention of scholars. It is generally recognized as one of the most important factors affecting implant bone union. This study intends to observe in vitro high glucose on MC3T3-E1 cell proliferation, osteogenic differentiation, and analysis of PI3K/Akt signal pathway in the regulation mechanism; from in vivo experiments, through the model of diabetic rats, detect the blood glucose levels of rats bone around the implant and changes of integrin alpha 5 beta 1 and fibronectin (the expression level of FN), comprehensive evaluation of the impact of the mechanisms of diabetes mellitus combined with bone implant. Materials and methods: in vitro: the PI3K/AKT pathway in osteogenic differentiation of MC3T3-E1 cells under high glucose condition according to the different literature selected four kinds of radical concentrations of glucose: 5.5mmol/L, 15.5mmol/L, 25.5mmol/L, 35.5mmol/L, to simulate the normal physiological concentration of glucose in the body and in different degrees of high blood glucose concentration, and according to whether adding PI3K/AKT to LY294002 pathway inhibitors into eight groups: 1) 5.5mM glucose concentration group (5.5mM-); 2) 15.5mM sugar concentration group (15.5mM-); 3) 25.5mM sugar concentration group (25.5mM-); 4) 35.5mM sugar concentration group (35.5mM-); 5) 5.5mM sugar concentration +LY294002 group (5.5mM+); 6) +LY294002 group (1 5.5mM glucose concentration 15.5mM+); 7) 25.5mM sugar concentration +LY294002 group (25.5mM+); 8) 35.5mM sugar concentration +LY294002 group (35.5mM+); the 5.5mM sugar concentration group (5.5mM) as the control group. Methyl thiazolyl four triazole (MTT) method for the determination of 1D, 3D cell proliferation; alkaline phosphatase (ALP) detection of 3D activity, cell differentiation of 7D; alizarin red staining 7d, 14d cells secrete calcium nodules; Determination of fluorescence real-time quantitative PCR gene Run mRNA and OCN mRNA were expressed in 3D and 7d Western blot (Western; blot) for detection of 3D and phosphorylation of 7D protein kinase (P Akt) expression. In vivo experiment: the mechanism of osseointegration around implants in diabetic rats. A total of 33 healthy male ZDF (Zucker diabetic fatty) rats were randomly divided into 3 groups, 11 rats in each group, and 2 implants in each of the 3 month old rats. A group: control group, ZDF rats were injected with normal saline, direct implants (11 rats, 22 implants); group B: ZDF rats received exenatide release nanospheres treatment (subcutaneous injection, 0.74%, 0.1m]/100g), and at the same time implants (11 rats rats, 22 implants); group C: ZDF rats received exenatide release nanospheres treatment (subcutaneous injection, 0.74%, 0.1ml/100g), and serum glucose maintained at a constant level (less than 16mmol/L), and then implants (11 rats, 22 implants). Implant after surgery, in 7d, 14d, 30d, 60d rats were killed in batches, surgical removal of bilateral femur to net muscle, mucosa and soft tissue, then use bone implant drill cutting range cut near 3mm, resulting in a rectangular bone implant containing specimens (section 7d, the number of specimens of n = 4 / n, 14d, 30d, 60d, the number of specimens were n=6 / N). The bone metabolism status around the implants was observed by hard tissue slices and HE staining. The expression of integrin alpha 5 beta 1 and fibronectin around the implants were detected by immunohistochemistry. Results: MTT results showed that in the 24h, compared with the control group, 15.5mM- group and 25.5mM- absorbance values showed no significant change (PO.05); however, the absorbance of 35.5mM- group was significantly lower than the control group, the difference was statistically significant (P0.05); in the 72h, compared with the control group, the absorbance of 15.5mM- the value of the group increased significantly, the difference was statistically significant (P0.05); however, the absorbance of 25.5mM- and 35.5mM- group was significantly lower than the control group, and the difference was statistically significant (P0.05). In addition, at each time point, the absorbance using four groups of cells treated with LY294002 values were significantly decreased compared with the control group, the difference was statistically significant (P0.05) ALP experimental results show that, in the 3D, compared with the control group, 15.5mM- group, 25.5mM- group and 35.5mM- group absorbance values were not significant change, no statistically significant difference between the absorbance (P0.05), however, adding four groups of cells treated with LY294002 were significantly lower than the control group, the difference was statistically significant (P0.05); in the 7d, the 15.5mM- group showed the highest absorbance value, and compared with the control group with significant difference (P0.05), however. 25.5mM- group and mM- group of 35.5 absorbance values significantly decreased, the difference was statistically significant (P0.05). In addition, the absorbance values of the four groups treated by LY294002 were significantly lower than those of the control group (P0.05), and the absorbance values of the 15.5 mM+ group were higher than those of the 5.5 mM+ group, the 25.5 mM+ group and the 35.5 mM+ group, and the difference was statistically significant (P0.05). Alizarin red staining showed that in the 7d group, 15.5mM- integral absorbance value of calcium nodules was significantly higher than the control group and the experimental group, the difference was statistically significant (P0.05), at the same time, the integral absorbance of 25.5mM- group and 35.5mM- group of calcium nodules value is higher than that of the control group, and the difference had statistical differences (P0.05) in addition. The integral absorbance of calcium nodules, four groups of cells treated with LY294002 were significantly lower than the control group, the difference was statistically significant (P0.05); in the 14d, compared with the control group, 15.5mM- group of integral absorbance value to calcium nodules increased significantly, the difference was statistically significant (P0.05), however, the integral absorbance of 25.5mM- group 35.5mM- group and calcium nodules were compared with the control group had no significant difference (P0.05), also, the calcium nodules integral absorbance of four groups of cells treated with LY294002 were significantly lower than the control group, the difference has statistical significance Yi (P
【學(xué)位授予單位】：山東大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2015
【分類號(hào)】：R587.2;R783

【共引文獻(xiàn)】

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本文編號(hào)：1338590