本文關(guān)鍵詞：氟對(duì)破骨細(xì)胞增殖的影響及可能的分子機(jī)制　出處：《中南大學(xué)》2012年博士論文　論文類(lèi)型：學(xué)位論文

  更多相關(guān)文章： 氟化鈉 氟斑牙 破骨細(xì)胞 骨質(zhì)疏松 氟化鈉 破骨細(xì)胞 增殖 TRAP 氟化鈉 破骨細(xì)胞 影響 MCM3

【摘要】：第一章慢性氟中毒對(duì)大鼠骨相損傷的影響 目的：通過(guò)慢性染氟,觀察氟對(duì)大鼠骨相(牙和骨骼)損傷的影響,探討破骨細(xì)胞與氟中毒導(dǎo)致骨相變化的可能關(guān)系。 方法：本實(shí)驗(yàn)采用Wistar大鼠染氟干預(yù)(劑量分別是0mg/L、25mg/L、50mg/L、100mg/L、150mg/L)的方法,染氟6個(gè)月,分別通過(guò)體視顯微鏡、病理學(xué)、X線以及染氟大鼠的氟的負(fù)荷量等幾個(gè)方面檢測(cè)氟中毒大鼠的特征性指標(biāo)。 結(jié)果：①大鼠一般狀況的變化,隨著染毒時(shí)間的延長(zhǎng),染氟第2個(gè)月時(shí),100mg/L組和150mg/L組大鼠表現(xiàn)出精神萎靡,食欲減弱；染氟第5個(gè)月,50mg/L組大鼠出現(xiàn)上述表現(xiàn),隨著染氟時(shí)間的延長(zhǎng),其表現(xiàn)更加明顯；實(shí)驗(yàn)?zāi)┢诖笫篌w重與實(shí)驗(yàn)前相比,25mg/L組與空白組比較,大鼠體重值要比空白組低,但統(tǒng)計(jì)學(xué)顯示,差異不具有顯著性,(P0.05)；50mg/L組和100mg/L組與對(duì)照組相比較體重增長(zhǎng)曲線基本一致,而150mg/L組從第八周開(kāi)始,體重增長(zhǎng)趨勢(shì)逐漸減弱,與空白組比較,差異具有顯著性,(P0.05)。②大鼠牙齒的變化,大鼠切齒4顆,上齒短,下齒長(zhǎng)而尖。對(duì)照組大鼠切齒呈均勻的淡黃色,表面光滑有光澤。實(shí)驗(yàn)組大鼠個(gè)體差異較大,100mg/L、150mg/L組大鼠有的在3個(gè)月左右就可出現(xiàn)氟斑牙,輕者牙表面黃、白相間,白堊條紋清晰,尚有一定光澤。隨時(shí)間的延長(zhǎng),氟斑牙癥狀逐漸加重,牙齒表面呈無(wú)光澤粉筆樣白色斑(白堊狀)。有的大鼠牙齒表面出現(xiàn)小溝、裂紋、或部分脫落,牙齒呈鋸齒狀嚴(yán)重缺損。說(shuō)明染氟劑量對(duì)氟斑牙的形成程度有一定的影響,表現(xiàn)出劑量和時(shí)間依賴性。③X線征象變化：100mg/L、150mg/L組骨盆的骶髂關(guān)節(jié)改變最多見(jiàn)。X線征象檢查顯示骨盆改變出現(xiàn)最早,2個(gè)月時(shí)少數(shù)幾例見(jiàn)骨紋模糊,3個(gè)月后骨紋模糊、紊亂明顯增加骨密度增高,染氟6個(gè)月時(shí),染氟150mg/L組部分髓腔密度降低,說(shuō)明高劑量染氟導(dǎo)致大鼠骨小梁的骨吸收增強(qiáng),表現(xiàn)出骨質(zhì)疏松。不同劑量氟干預(yù)導(dǎo)致結(jié)果不同,主要表現(xiàn)為骨硬化,高劑量表現(xiàn)出骨質(zhì)疏松。④大鼠股骨組織形態(tài)計(jì)量參數(shù)分析：150mg/L組股骨干骺端平均骨小梁密度(MTPD)及平均骨小梁厚度(MTPT)明顯減小,差異有顯著性(P0.05),說(shuō)明高劑量可以造成骨質(zhì)疏松的表現(xiàn)。⑤組織病理學(xué)改變：150mg/L組：骨板彎曲變形,排列不規(guī)則；骨陷窩與骨基質(zhì)之間的裂隙較多,骨細(xì)胞數(shù)量減少,胞核皺縮或消失,骨小管細(xì)小甚至消失；骨小梁排列紊亂,數(shù)量減少,間距變大,寬度變窄,連接呈網(wǎng)狀；成骨細(xì)胞成層排列,數(shù)量增多,破骨細(xì)胞數(shù)量較其他劑量組明顯增多,胞體肥大,細(xì)胞核為多個(gè)。⑥氟負(fù)荷量的變化：染氟6個(gè)月后尿液中氟離子隨著染氟濃度的升高而呈上升趨勢(shì),與對(duì)照組比較,差異具有顯著性(P0.05)；血液中氟離子在6個(gè)月時(shí),染氟組與對(duì)照組比較,氟離子濃度值輕微上升,但統(tǒng)計(jì)學(xué)比較差異不具有顯著性(P0.05)；大鼠股骨中氟離子濃度值與對(duì)照組比較,25mg/L組有輕微上升,但沒(méi)有統(tǒng)計(jì)學(xué)意義,而50mg/L、100mg/L、150mg/L三組氟離子上升比較明顯,差異具有顯著性(P0.05)；大鼠下切牙的氟離子濃度值與對(duì)照組比較,各染氟組都明顯升高,差異具有顯著性(P0.05)。 結(jié)論：染氟后大鼠體內(nèi)氟負(fù)荷量隨著時(shí)間和劑量基本呈遞增趨勢(shì)；高劑量長(zhǎng)時(shí)間染氟導(dǎo)致骨質(zhì)疏松,與破骨細(xì)胞的功能活躍有一定的關(guān)系。 第二章氟對(duì)離體培養(yǎng)破骨細(xì)胞增殖的影響 目的：探討sRANKL對(duì)小鼠RAW264.7細(xì)胞的誘導(dǎo)分化及氟對(duì)RAW264.7細(xì)胞增殖的影響。 方法：本實(shí)驗(yàn)采用體外培養(yǎng)破骨細(xì)胞,以sRANKL誘導(dǎo)RAW264.7細(xì)胞進(jìn)行鑒定,以氟化鈉0到160mg/L范圍內(nèi)給出13個(gè)劑量組進(jìn)行染氟,采用噻唑藍(lán)(MTT)法,觀察存活細(xì)胞數(shù)量,并繪制增殖曲線,篩選出與破骨細(xì)胞增殖相關(guān)的4個(gè)劑量組,分別是0、2、10、50mg/L組,用HE染色、甲苯胺藍(lán)染色、TRAP染色以及掃描電鏡和透射電鏡對(duì)破骨細(xì)胞的誘導(dǎo)分化及增殖作用進(jìn)行了形態(tài)學(xué)和功能方面的鑒定。 結(jié)果：①誘導(dǎo)前RAW264.7細(xì)胞呈星形、圓形或不規(guī)則形,細(xì)胞核1-2個(gè)。誘導(dǎo)后外形仍然呈不規(guī)則形,但圓形細(xì)胞基本消失,細(xì)胞核為多個(gè)。TRAP染色陽(yáng)性細(xì)胞為細(xì)胞質(zhì)鮮紅色或者淡紅色,細(xì)胞核2-3個(gè)多見(jiàn),形態(tài)呈多突起不規(guī)則形。②誘導(dǎo)后倒置顯微鏡觀察與HE染色、甲苯胺藍(lán)染色表明與牛骨磨片共培養(yǎng)發(fā)現(xiàn)經(jīng)過(guò)誘導(dǎo)分化后的RAW264.7細(xì)胞吸收陷窩明顯增多,組間比較差異具有顯著性(P0.05)。③誘導(dǎo)后電鏡結(jié)果顯示,RAW264.7細(xì)胞邊緣呈指狀、刺狀或不規(guī)則的突起,外形不規(guī)則,細(xì)胞密度較低的是已分化成熟的破骨細(xì)胞,能夠形成吸收陷窩。④染氟后通過(guò)光鏡、電鏡及MTT法檢測(cè),說(shuō)明當(dāng)氟化鈉濃度低于2mg/L時(shí),對(duì)RAW264.7細(xì)胞生長(zhǎng)無(wú)明顯影響；當(dāng)氟化鈉濃度介于2mg/L與10mg/L時(shí),RAW264.7細(xì)胞增殖數(shù)量明顯增加；而當(dāng)氟化鈉濃度高于50mg/L時(shí),RAW264.7細(xì)胞增殖受到明顯抑制；組間比較差異具有顯著性(P0.05)。 結(jié)論：明確TRAP染色可以作為破骨細(xì)胞一種形態(tài)學(xué)鑒定方法；低劑量的氟可以促進(jìn)體外培養(yǎng)小鼠破骨細(xì)胞增殖,隨劑量增加其促進(jìn)作用減弱；高劑量氟對(duì)破骨細(xì)胞增殖有抑制作用。 第三章氟對(duì)破骨細(xì)胞作用的可能分子機(jī)制 目的：探討氟對(duì)MCM3基因表達(dá)和分布的影響以及MCM3對(duì)破骨細(xì)胞增殖活力的影響。 方法：本實(shí)驗(yàn)采用體外培養(yǎng)破骨細(xì)胞,用免疫熒光技術(shù)、Western blot以及半定量RT-PCR的方法,檢測(cè)不同劑量0、2、10、50mg/L的氟對(duì)MCM3mRNA以及蛋白的影響；以及染氟6個(gè)月大鼠,用ELISA法檢測(cè)MCM3在染氟大鼠血清中的變化；通過(guò)MTT法檢測(cè)MCM3對(duì)破骨細(xì)胞增殖活力的影響。 結(jié)果：①通過(guò)RT-PCR檢測(cè)比較各組之間MCM3mRNA的表達(dá)量,2mg/L組與空白組之間表達(dá)量略高,但無(wú)統(tǒng)計(jì)學(xué)意義(P0.05)；10mg/L組與空白組相比,MCM3mRNA的表達(dá)量明顯升高(P0.05)；50mg/L組與空白組相比較MCM3mRNA的表達(dá)量明顯下降(P0.05)；各組間比較發(fā)現(xiàn)50mg/L組與其他各組具有顯著性差異(P0.05)。②Western-blot結(jié)果顯示2mg/L、l0mg/L組與空白組相比較,MCM3蛋白表達(dá)量略高于空白組(P0.05),50mg/L組與空白組相比較,MCM3蛋白表達(dá)量略低于空白組(P0.05),2mg/L組與10mg/L組相比較,2mg/L組蛋白表達(dá)量略高,但無(wú)統(tǒng)計(jì)學(xué)意義(P0.05)。③免疫熒光結(jié)果顯示MCM3蛋白表達(dá)0、2、10mg/L各組主要表達(dá)在細(xì)胞核,有微量在細(xì)胞質(zhì),表達(dá)量依次增強(qiáng)；50mg/L組主要表達(dá)在細(xì)胞質(zhì),細(xì)胞核有少量表達(dá),表達(dá)強(qiáng)度較弱。④ELISA結(jié)果顯示高劑量染氟150mg/L組,在染氟6個(gè)月時(shí),MCM3的表達(dá)量與其他各組比較差異均有統(tǒng)計(jì)學(xué)意義,P0.05。⑤體外破骨細(xì)胞培養(yǎng)48h內(nèi),染氟組在24h～36h,與空白組比較,破骨細(xì)胞增殖活力明顯提高,有統(tǒng)計(jì)學(xué)意義,P0.05；MCM3抗原組在培養(yǎng)24h,增殖活力提高,與空白組比較有統(tǒng)計(jì)學(xué)意義,P0.05；當(dāng)氟與MCM3抗原共同作用時(shí),在破骨細(xì)胞培養(yǎng)12h～36h,增殖活力最明顯,與空白組比較都有統(tǒng)計(jì)學(xué)意義,P0.05；當(dāng)MCM3抗體作用于破骨細(xì)胞,在培養(yǎng)24h～48h時(shí),細(xì)胞增殖活力具有下降趨勢(shì),與氟+抗原組比較,差異具有統(tǒng)計(jì)學(xué)意義,P0.05。說(shuō)明MCM3抗原相對(duì)于抗體在早期就具有刺激破骨細(xì)胞增殖的趨勢(shì),隨著作用時(shí)間的延長(zhǎng),MCM3抗原加強(qiáng)了破骨細(xì)胞的增殖作用,在染氟晚期,破骨細(xì)胞增殖能力也與MCM3有一定的關(guān)系。 結(jié)論：不同劑量的氟對(duì)體外培養(yǎng)破骨細(xì)胞MCM3的表達(dá)量不同,基本表現(xiàn)出2mg/L、10mg/L染氟組促進(jìn)MCM3的表達(dá),50mg/L染氟組明顯抑制了MCM3的表達(dá),從10mg/L氟劑量開(kāi)始出現(xiàn)抑制作用,隨劑量增加促進(jìn)作用逐漸減弱,50mg/L基本達(dá)到毒性反應(yīng)；高劑量150mg/L氟對(duì)在體MCM3表達(dá)具有明顯增強(qiáng)作用,說(shuō)明促進(jìn)破骨細(xì)胞增殖,其機(jī)制有待進(jìn)一步研究；MCM3在一定時(shí)間內(nèi)對(duì)體外破骨細(xì)胞增殖有促進(jìn)作用,但具體機(jī)制需要進(jìn)一步研究。
[Abstract]:The effect of chronic fluorosis in the first chapter on the injury of bone in rats
Objective: To observe the effect of fluorine on the injury of bone phase (tooth and bone) in rats by chronic fluorine dye, and to explore the possible relationship between osteoclast and fluorosis.
Methods: the Wistar rats were exposed to fluoride intervention (doses were 0mg/L, 25mg/L, 50mg/L, 100mg/L, 150mg/L) method of fluoride for 6 months, respectively, through the microscope, pathology, X-ray and several characteristic indexes in rats exposed to fluorine fluorine load on detection of fluorosis rats.
Results: the changes of general condition of rats, with the extension of exposure time, the fluoride at second months, 100mg/L group and 150mg/L group rats showed listlessness, decreased appetite; fluoride fifth months, rats in the 50mg/L group appear in the show, with extended exposure to fluoride, which is more obvious compared with the experimental rats; body weight before the end of the experiment, 25mg/L group compared with the control group, the rats weight value lower than the control group, but the statistics showed that the difference was not significant, (P0.05); 50mg/L group and 100mg/L group compared with the control group, the weight gain of Qu Xianji consistent, while the 150mg/L group from the beginning of the eighth weeks, weight increased gradually, compared with the control group, the difference was significant (P0.05). The changes of rat teeth, tooth rat 4 teeth, teeth short, long and sharp teeth. The rats in control group were evenly cutting pale yellow, shiny surface. The experimental group In individual differences, 100mg/L, 150mg/L group of rats in 3 months or so can appear dental fluorosis, tooth surface light yellow, white chalk stripe is clear, there is a certain luster. With the extension of time, dental fluorosis symptoms gradually worsened, the tooth surface was dull chalk like white spots (Bai Ezhuang). The minor groove, there some rat tooth surface crack, or shedding of jagged teeth defect. That has a certain impact on the formation of fluoride concentration degree of dental fluorosis, showed a dose and time dependent manner. The X-ray signs of change: 100mg/L, 150mg/L group of pelvic sacroiliac joint change is the most common. X-ray examination showed pelvic changes the earliest, 2 months, a few cases of bone lines blurred, 3 months after the bone pattern fuzzy disorder obviously increase the bone density increased, fluoride at 6 months, the fluoride group 150mg/L part of the medullary cavity density decreased, indicating a high dose fluoride Guide Absorption induced rat trabecular bone increased, showed osteoporosis. Different doses of fluoride intervention leads to different results, mainly for bone sclerosis, high dose showed osteoporosis. Analysis of the rat femur histomorphometric parameters: group 150mg/L femoral metaphyseal mean trabecular bone density (MTPD) and the average bone Liang Houdu (MTPT) was significantly reduced, there were significant differences (P0.05), high dose can cause osteoporosis. The pathological changes: 150mg/L group: the bending deformation of the bone plate, irregular arrangement; fissure more between the lacunae and bone matrix, bone cells decreased, nucleus shrinkage or disappearance fine, canaliculi or even disappear; reduce the number of trabecular derangement, spacing becomes larger, width, connected with reticulate; osteoblast layers, the number increased, the number of osteoclasts than other dose groups significantly increased, the cell body hypertrophy, fine The nucleus is multiple. The change of fluorine load: fluoride after 6 months in the urine fluoride with increasing fluoride concentration increased, compared with the control group, the difference was significant (P0.05); the blood fluoride in 6 months, fluoride group compared with the control group and the fluorine ion concentration value increased slightly, but the difference was not significant (P0.05); compared with the control group of fluorine ion concentration in the rat femur, 25mg/L group has increased slightly, but not statistically significant, while 50mg/L, 100mg/L, 150mg/L three groups of fluorine ion rise is more obvious, the difference was significant (P0.05); rat incisor fluoride concentration values compared with the control group, the fluoride group were significantly increased, the difference was significant (P0.05).
Conclusion: fluoride load in rats increases basically with time and dose after exposure to fluoride. High dose of fluoride for a long time can lead to osteoporosis, which is related to the functional activity of osteoclasts.
The effect of fluorine on the proliferation of vitro cultured osteoclasts in the second chapter
Objective: To investigate the effect of sRANKL on the induced differentiation of mouse RAW264.7 cells and the effect of fluorine on the proliferation of RAW264.7 cells.
Methods: this experiment used cultured osteoclasts in vitro by sRANKL induced RAW264.7 cells were identified by sodium fluoride in the range of 0 to 160mg/L are given 13 doses of fluoride, methyl thiazolyl tetrazolium (MTT) method, observe the number of surviving cells, and draw the growth curve, screened 4 dose groups associated with osteoclast cell proliferation, respectively 0,2,10,50mg/L group, with HE staining, toluidine blue staining, differentiation and proliferation induced by TRAP staining and scanning electron microscopy and transmission electron microscopy of osteoclasts were identified by morphological and functional aspects.
Results: before induction of RAW264.7 cells with a star shaped, round or irregular shape, nuclear 1-2. After induction of appearance is still irregular, but round cells disappeared, the nucleus for multiple.TRAP staining positive cells were bright red or pale red, a rare form of nuclear 2-3, showed irregular projections after induction was observed with HE. The inverted microscope staining, toluidine blue staining showed that co cultured with bovine bone slices found after induction of differentiation of RAW264.7 cells after resorption increased significantly, the difference between groups was significant (P0.05). The results showed induction after RAW264.7 cells at the edge with a finger, spiny or irregular projection, irregular shape, cell density is lower in the differentiation of mature osteoclasts, can be formed by light microscopy. The resorption of fluoride detection, electron microscope and MTT method, when the concentration of sodium fluoride is less than 2mg/L When the concentration of sodium fluoride was between 2mg/L and 10mg/L, the proliferation of RAW264.7 cells increased significantly. When the concentration of sodium fluoride was higher than 50mg/L, the proliferation of RAW264.7 cells was significantly inhibited, and the difference between groups was significant (P0.05). When the concentration of sodium fluoride was between 10mg/L and 50mg/L, the proliferation of RAW264.7 cells was significantly inhibited.
Conclusion: TRAP staining can be used as a morphological identification method for osteoclasts. Low dose fluoride can promote the proliferation of osteoclasts in vitro, and its promotion effect decreases with the increase of dose. High dose fluoride inhibits the proliferation of osteoclasts.
The possible molecular mechanism of fluorine effect on osteoclast in the third chapter
Objective: To investigate the effect of fluorine on the expression and distribution of MCM3 gene and the effect of MCM3 on the proliferation of osteoclast.
Methods: this experiment used cultured osteoclasts in vitro by immunofluorescence, Western blot and semi quantitative RT-PCR method, detection of different doses of 0,2,10,50mg/L and the effects of fluoride on MCM3mRNA protein; and fluoride 6 months rats were detected by ELISA MCM3 staining in the changes of serum fluoride in rats by impact; detection of MCM3 MTT method to break the proliferation activity of osteoblasts.
Results: the expression of MCM3mRNA was detected by RT-PCR between the groups were compared between 2mg/L group and control group, the expression is slightly higher, but there was no statistical significance (P0.05); 10mg/L group compared with the control group, the expression of MCM3mRNA was significantly increased (P0.05); 50mg/L group compared with the control group the expression of MCM3mRNA was significantly decreased (P0.05); comparison between groups showed that 50mg/L group had a significant difference with other groups (P0.05). The Western-blot results showed that 2mg/L, l0mg/L group compared with the control group, MCM3 protein expression was slightly higher than that of the control group (P0.05), 50mg/L group compared with the control group, the expression of MCM3 protein was slightly lower than that of the control group (P0.05), 2mg/L group and 10mg/L group compared to 2mg/L group, the protein expression is slightly higher, but there was no statistical significance (P0.05). The immunofluorescence results showed that 0,2,10mg/L expression of MCM3 protein were mainly expressed in the nucleus, trace expression in the cytoplasm. In order to enhance; group 50mg/L mainly expressed in the cytoplasm, the nucleus has a small amount of expression, the expression intensity is weak. The ELISA results showed that high dose fluoride group 150mg/L, fluoride in 6 months, the expression of MCM3 and the other groups were statistically significant P0.05. in vitro osteoclast culture in 48h fluoride group from 24h to 36h, compared with the control group, osteoclast proliferation activity increased significantly, with statistical significance, P0.05 group; MCM3 antigen in cultured 24h proliferation activity increased, with statistical significance, compared with the control group P0.05; when the interaction of fluoride and MCM3 antigen, 12h ~ 36h in cultured osteoclasts, the most obvious proliferation activity, compared with the control group had statistical significance, P0.05; when the MCM3 antibody effect on osteoclasts cultured in 24h ~ 48h, cell proliferation activity has decreased, compared with fluoride + antigen group, the difference was statistically significant, P0.05. said The MCM3 antigen relative to the antibody has the trend of stimulating the proliferation of osteoclasts at the early stage. With the prolongation of the action time, MCM3 antigen strengthens the proliferation of osteoclasts, and the ability of osteoclast proliferation is also related to MCM3 in the late stage of fluoride exposure.
Conclusion: different doses of fluoride on osteoclasts cultured in vitro expression of MCM3 was different, 2mg/L showed the expression of 10mg/L, promote MCM3 fluoride group, 50mg/L fluoride group significantly inhibited the expression of MCM3, 10mg/L from the fluoride dose began to inhibit the promotion, with gradually weakened along with the increase of the dose, reached in 50mg/L toxicity; high dose fluoride 150mg/L has obvious enhancement effect on expression of MCM3 in vivo, that promotes osteoclast proliferation, its mechanism needs further study; MCM3 in a certain period of time in vitro osteoclast proliferation promoting effect, but the specific mechanism needs further study.

【學(xué)位授予單位】：中南大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2012
【分類(lèi)號(hào)】：R329

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