本文選題：多發(fā)性骨髓瘤 + 骨髓瘤骨病�。� 參考：《廣西醫(yī)科大學(xué)》2016年博士論文

【摘要】：骨髓瘤骨病(MBD)是MM患者的最常見(jiàn)的并發(fā)癥之一。MBD發(fā)生的主要機(jī)制:在骨髓微環(huán)境中,瘤細(xì)胞與骨髓基質(zhì)細(xì)胞(BMSCs)通過(guò)RANKL/RANK等經(jīng)典途徑、巨噬細(xì)胞炎癥蛋白-1α(MIP-1α)等非經(jīng)典途徑的信號(hào)通路,增強(qiáng)破骨細(xì)胞(OC)的數(shù)量、抑制成骨細(xì)胞(OB)的功能,最后導(dǎo)致溶骨性損害。本人前期研究及國(guó)內(nèi)外最近研究報(bào)道MIP-1α不僅有增加OC的數(shù)量和增強(qiáng)OC的功能,還有抑制OB的分化和成熟,但抑制OB的具體機(jī)制不明。骨硬化蛋白(sclerostin)是SOST基因的表達(dá)產(chǎn)物,參與骨形成調(diào)節(jié),決定骨重建過(guò)程中的骨量和結(jié)構(gòu),是Wnt/β-信號(hào)通路的重要抑制劑,而Wnt/β-信號(hào)通路在介導(dǎo)OB分化、成熟及功能調(diào)節(jié)中是非常重要的。最近研究報(bào)道:MM患者外周血sclerostin增高,但其增多的機(jī)制以及與MM患者的生物學(xué)特征尚不明確。本研究試圖通過(guò)探討MBD患者骨髓血漿及骨髓瘤細(xì)胞株MIP-1α和sclerostin蛋白的表達(dá),以此探明這兩種蛋白與患者的臨東快氮分期、生化特征、預(yù)后及兩者之間的關(guān)系等。通過(guò)從美國(guó)國(guó)立生物技術(shù)信息中心(GEO)的共享數(shù)據(jù)庫(kù)中下載MBD相關(guān)的基因芯片表達(dá)數(shù)據(jù)譜GSE754和GSE755,運(yùn)用生物信息學(xué)相關(guān)工具進(jìn)行數(shù)據(jù)和文獻(xiàn)挖掘,通過(guò)大數(shù)據(jù)分析MIP-1α和sclerostin蛋白是否具有一定的關(guān)聯(lián)性。進(jìn)一步在體外驗(yàn)證這兩種蛋白的相互關(guān)系,為MBD患者的防治開(kāi)拓新思路和提供理論依據(jù)。本論文主要從如下三方面進(jìn)行探討。第一部分MIP和sclerostin在骨髓瘤骨病患者中的表達(dá)及與臨東目的:本研究旨在探討MIP-1α和sclerostin在MBD中的表達(dá),MIP-1α和sclerostin與MBD分級(jí)、ISS臨東及兩者相互之間的關(guān)系。方法:以53名MBD患者(其中女24名,男29名),人多發(fā)性骨髓瘤細(xì)胞株RPMI-8226、H929及30名白細(xì)胞減少癥、免疫性血小板減少癥患者為研究對(duì)象。酶聯(lián)免疫吸附法(ELISA)定量檢測(cè)骨髓血漿MIP-1α和sclerostin蛋白的水平;RT-PCR技術(shù)檢測(cè)MIP-1α和sclerostin蛋白的m RNA表達(dá);電化學(xué)發(fā)光免疫法測(cè)量甲狀旁腺素(PTH)和1,25(OH)2Vit D3的水平,全自動(dòng)生化分析儀檢測(cè)患者的各項(xiàng)常規(guī)生化指標(biāo)等。實(shí)驗(yàn)數(shù)據(jù)以均數(shù)±標(biāo)準(zhǔn)差表示,使用SPSS18.0統(tǒng)計(jì)學(xué)軟件進(jìn)行分析。結(jié)果:27例患者的sclerostin水平升高,37例患者中MIP-1α蛋白的水平明顯升高。MBD患者的MIP-1α(153.35±81.09 pg/ml)和sclerostin(539.42±201.86 pg/ml)蛋白濃度要高于對(duì)照組(t=6.85和8.26,p均為0.00)。體外骨髓瘤細(xì)胞株RPMI-8226、H929培養(yǎng)上清液中MIP-1α和sclerostin蛋白的水平與空白對(duì)照組相比均明顯增高(t值分別為23.52,13.42;P值均為0.000.01),RT-PCR的結(jié)果分析也證實(shí)了大部分的MBD患者骨髓單個(gè)核細(xì)胞(BMMNCs)及兩種骨髓瘤細(xì)胞株均表達(dá)這兩種蛋白,但表達(dá)的量不一致。臨抗ISS分期3期患者中的MIP-1α(173.81±97.74 pg/ml)和sclerostin蛋白(0.61±0.20ng/ml)的表達(dá)水平明顯高于2期的患者(MIP-1α:117.73±54.35 pg/ml,sclerostin:0.42±0.18 ng/ml)(p值分別為0.01、0.06);MBD分級(jí)C組患者的MIP-1α蛋白(MIP-1α170.37±103.69 pg/ml)和sclerostin(0.60±0.02 pg/ml)水平也明顯高于A+B組(MIP-1α:119.82±38.15 pg/ml,sclerostin:0.45±0.19 ng/ml))(P值均小于0.01)。sclerostin水平與MIP-1α蛋白(r=0.720,p=0.000.001),β2-MG(r=0.467,p=0.000.001,LDH(r=0.453,p=0.001),a Ca水平(r=0.313,p=0.023)之間呈明顯的正相關(guān),而sclerostin蛋白與b ALP(r=-0.578,p=0.000.001),HB(r=-0.412,p=0.002),ALB(r=-0.388,p=0.004)之間呈負(fù)相關(guān);sclerostin、MIP-1α蛋白的水平與MBD分級(jí)(r=0.439和0.358,p=0.001和0.008)和ISS分期(r=0.436和0.323,p=0.001、0.018)呈正相關(guān),高水平(0.54ng/ml)的sclerostin蛋白的MBD患者的中位生存時(shí)間也要短于低水平的患者(X2=7.376,p=0.007),而高水平(153.71pg/ml)的MIP-1α蛋白的MBD患者的中位生存時(shí)間雖短于低水平的患者,但兩者比較無(wú)統(tǒng)計(jì)學(xué)差異(χ2=2.94,p=0.086)。雙重線性回歸結(jié)果提示ISS分期、sclerostin蛋白,β2-MG,MIP-1α蛋白是MBD分級(jí)獨(dú)立的預(yù)后不良因素。結(jié)論:1.MIP-1α、sclerostin在MBD患者骨髓中水平增高、骨髓瘤細(xì)胞系能分泌這兩種蛋白,但不同細(xì)胞系表達(dá)水平不一定相同;2.MIP-1α、sclerostin與臨床ISS分期、MBD分級(jí)、與反應(yīng)瘤負(fù)荷的相關(guān)指標(biāo)β2-MG、LDH水平呈正相關(guān),而與b ALP、HB、ALB則呈負(fù)相關(guān)。3.高水平(0.54ng/ml)的sclerostin的MBD患者的中位生存時(shí)間要短于低水平的MBD患者.4.MIP-1α與sclerostin呈明顯的正相關(guān)。目的:采用生物信息學(xué)各種軟件和在線工具進(jìn)行篩選MBD的相關(guān)基因,并對(duì)其進(jìn)行數(shù)據(jù)和文獻(xiàn)挖掘,進(jìn)一步通過(guò)大數(shù)據(jù)了解MIP-1α與sclerostin是否具有一定的關(guān)聯(lián)性。方法:以MBD相關(guān)的兩組患者基因芯片表達(dá)數(shù)據(jù)譜GSE754(139例有骨質(zhì)破壞的MM患者)和GSE755(34例無(wú)骨質(zhì)破壞的患者)為研究材料,運(yùn)用Gene Spring GX11.5軟件對(duì)基因芯片數(shù)據(jù)進(jìn)行差異基因分析,GATHER等分析工具注釋MBD相關(guān)差異基因可能的分子功能、參與的各種信號(hào)通路及通路富集,Cytosine軟件分析差異基因編碼蛋白質(zhì)之間的相互作用關(guān)系。結(jié)果:從GSE754和GSE755基因芯片數(shù)據(jù)中分析得到共173個(gè)樣本,經(jīng)Genesis軟件分析得出435個(gè)共同表達(dá)的差異基因,其中高表達(dá)的有286個(gè)基因,低表達(dá)的有149個(gè)基因。導(dǎo)入GATHER后發(fā)現(xiàn)這些差異基因主要與細(xì)胞增殖、鈣磷代謝、細(xì)胞周期,細(xì)胞粘附與遷移、細(xì)胞凋亡、蛋白酶體、MAPK、趨化因子信號(hào)通路、Erb B、細(xì)胞周期,細(xì)胞減速分裂、Wnt、T、B細(xì)胞信號(hào)通路、JakSTAT、Rho A/ROCK等信號(hào)通路有關(guān)。將差異基因?qū)隒ytosine軟件中分析,結(jié)果發(fā)現(xiàn)BMD相關(guān)基因編碼的蛋白質(zhì)間的相互聯(lián)系主要集中在NF-κB,PTK2B,ADD3,SPP1,IGF2,HSF2,HSF2,NTRK2,ADD3,GST6、CCL3、IL-6,Rh OA、sclerostin等基因上。結(jié)論:通過(guò)對(duì)基因芯片大數(shù)據(jù)進(jìn)行生物信息學(xué)相關(guān)分析篩選得出MIP-1α與sclerostin具有一定的關(guān)聯(lián)性,參與MBD的發(fā)生主要涉及到蛋白酶體、MAPK、Erb B、細(xì)胞周期,Wnt、Jak-STAT等信號(hào)通路。第二部分:骨髓瘤骨病相關(guān)基因的篩選及生物信息學(xué)分析目的:擬在體外通過(guò)細(xì)胞培養(yǎng),外源性給予MIP-1α和sclerostin、MIP-1α和sclerostin單抗增加或中和骨髓瘤細(xì)胞株RPMI-8226、H929高表達(dá)sclerostin/MIP-1α的水平,觀察該細(xì)胞的sclerostin/MIP-1α的水平變化。初步驗(yàn)證這兩種蛋白的關(guān)聯(lián)性。方法:以人骨髓瘤細(xì)胞系RPMI-8226、H929為研究對(duì)象,ELISA定量檢測(cè)各組細(xì)胞上清液中的MIP-1α和sclerostin蛋白水平,RT-PCR定量檢測(cè)各組細(xì)胞的MIP-1α和sclerostin m RNA水平。結(jié)果:兩組細(xì)胞上清液中加入MIP-1α后再培養(yǎng)24小時(shí),MIP-1α和sclerostin水平較不干預(yù)組明顯增高(p值均為0.00);加入MIP-1α單抗后,兩組細(xì)胞中的MIP-1α和sclerostin水平較不干預(yù)組明顯下降(p值分別為0.00和0.001);加入sclerostin及sclerostin單抗后,兩組細(xì)胞的MIP-1α水平較不干預(yù)組改變不明顯(p值均大于0.05),加入sclerostin后,兩組細(xì)胞的sclerostin水平明顯增高(p值均小于0.01),而加入sclerostin單抗后,兩組細(xì)胞的sclerostin水平明顯下降(p值均小于0.01)。結(jié)論:MIP-1α可介導(dǎo)骨髓瘤細(xì)胞分泌sclerostin,具體機(jī)制需進(jìn)一步研究�？傊�,本研究驗(yàn)證了sclerostin、MIP-1α兩種蛋白在大部分MBD患者骨髓中及骨髓瘤細(xì)胞株中呈高表達(dá),且與瘤負(fù)荷、MBD分級(jí)、ISS分期相關(guān),兩種蛋白呈明顯的正相關(guān)。通過(guò)從GEO下載基因芯片大數(shù)據(jù),運(yùn)用生物信息學(xué)相關(guān)軟件和在線工具進(jìn)一步驗(yàn)證了sclerostin、MIP-1α兩種蛋白有一定的關(guān)聯(lián)。在體外通過(guò)細(xì)胞培養(yǎng)技術(shù)驗(yàn)證了MIP-1α可能通過(guò)各種途徑促進(jìn)瘤細(xì)胞或骨髓微環(huán)境分泌sclerostin。這揭示了MIP-1α在MBD中抑制OB的功能可能是通過(guò)sclerostin來(lái)介導(dǎo)的可能機(jī)制。第三部分體外通過(guò)細(xì)胞培養(yǎng)驗(yàn)證MIP-1α和sclerostin的關(guān)系
[Abstract]:Myeloma osteopathy (MBD) is the main mechanism of one of the most common complications of MM patients: in the bone marrow microenvironment, tumor cells and bone marrow stromal cells (BMSCs) can enhance the number of osteoclast (OC) and inhibit osteoblast through the classical pathway of RANKL/RANK, such as RANKL/RANK and other classical pathways, such as macrophage inflammatory protein -1 alpha (MIP-1 alpha). The function of (OB), which eventually leads to osteolytic damage. My previous studies and recent studies at home and abroad have reported that MIP-1 alpha not only increases the number of OC and enhances the function of OC, but also inhibits the differentiation and maturation of OB, but the specific mechanism of the inhibition of OB is unknown. The bone sclerosis protein (sclerostin) is the expression product of the SOST gene, participates in the regulation of bone formation, and determines the bone. Bone mass and structure during the reconstruction are important inhibitors of the Wnt/ beta signaling pathway, and the Wnt/ beta signaling pathway is very important in mediating OB differentiation, maturation and functional regulation. Recent studies have reported that the peripheral blood sclerostin of MM patients is higher, but the mechanism of its increase and the biological characteristics of the patients with MM are not yet clear. This study attempts to use this study. To explore the expression of MIP-1 alpha and sclerostin protein in the bone marrow plasma and myeloma cell lines of MBD patients, in order to identify the two proteins and the patient's Near East fast nitrogen staging, biochemical characteristics, prognosis and the relationship between the two. The MBD related gene chip expression was downloaded from the shared database of the National Biotechnology Information Center (GEO) of the United States. Data spectrum GSE754 and GSE755, using bioinformatics related tools to carry out data and literature mining, through large data analysis whether MIP-1 alpha and sclerostin protein have a certain relevance. Further to verify the relationship between these two proteins in vitro, to open up new ideas and theoretical basis for the prevention and control of MBD patients. The following three aspects are discussed. Part 1: expression of MIP and sclerostin in patients with myeloma bone disease and its immediate East purpose: This study aims to explore the expression of MIP-1 alpha and sclerostin in MBD, MIP-1 alpha and sclerostin and MBD grading, ISS near the East and the relationship between the two. Methods: 53 MBD patients (24 women, 29 men), and more people. Hair myeloma cell lines RPMI-8226, H929 and 30 leukenia and immunological thrombocytopenia were studied. Enzyme linked immunosorbent assay (ELISA) was used to detect the level of MIP-1 alpha and sclerostin in bone marrow plasma; RT-PCR technique was used to detect the m RNA expression of MIP-1 A and sclerostin egg white; electrochemiluminescence immunoassay was used to measure the thyroid gland. The levels of parathyroid (PTH) and 1,25 (OH) 2Vit D3 were measured by an automatic biochemical analyzer. The experimental data were expressed with mean standard deviation, and the SPSS18.0 statistics software was used for analysis. Results: the level of sclerostin in 27 patients was elevated, and the level of MIP-1 alpha protein in 37 patients significantly increased MIP- in.MBD patients. The concentration of 1 alpha (153.35 + 81.09 pg/ml) and sclerostin (539.42 + 201.86 pg/ml) protein was higher than that in the control group (t=6.85 and 8.26, P was 0). The level of MIP-1 A and sclerostin protein in the culture supernatant of H929 was compared with that of the blank control group (t value was 23.52,13.42; P values were all), The results also showed that most of the MBD patients' bone marrow mononuclear cells (BMMNCs) and two myeloma cell lines expressed these two proteins, but the amount of expression was not consistent. The expression level of MIP-1 alpha (173.81 + 97.74 pg/ml) and sclerostin protein (0.61 + 0.20ng/ml) in the 3 stage patients with ISS staging was significantly higher than that of the 2 stage patients (MIP-1 A: 1). 17.73 + 54.35 pg/ml, sclerostin:0.42 + 0.18 ng/ml) (P value was 0.01,0.06), MIP-1 alpha protein (MIP-1 alpha 170.37 + 103.69 pg/ml) and sclerostin (0.60 + 0.02 pg/ml) in MBD graded C group were also significantly higher than that of the group (119.82 + 38.15, 0.19). R=0.720 (p=0.000.001), beta 2-MG (r=0.467, p=0.000.001, LDH (r=0.453, p=0.001), a Ca level (r=0.313, p=0.023) showed a negative correlation; .358, p=0.001, and 0.008) were positively correlated with ISS staging (r=0.436 and 0.323, p=0.001,0.018). The median survival time of the MBD patients with high level (0.54ng/ml) sclerostin protein was also shorter than that of low level patients (X2=7.376, p=0.007), while the median survival time of the high level (153.71pg/ml) MIP-1 alpha protein was shorter than the low level. But there was no statistical difference between the two (x 2=2.94, p=0.086). The results of double linear regression suggested that ISS staging, sclerostin protein, beta 2-MG, MIP-1 alpha protein were independent prognostic factors of MBD classification. Conclusion: 1.MIP-1 a, sclerostin in the bone marrow of MBD patients, the two proteins can be secreted by the bone myeloma cell line, but the expression of different cell lines is expressed. The level of 2.MIP-1 alpha, sclerostin and clinical ISS staging and MBD grading were positively correlated with the level of the response to the response to the tumor load, the level of LDH was positively correlated with the B ALP, HB, ALB, and the median survival time of the patients was shorter than the low level. Objective: to select the related genes of MBD by using various bioinformatics software and online tools, and to carry out data and literature mining, and to further understand whether there is a certain correlation between MIP-1 alpha and sclerostin through large data. Methods: the data spectrum GSE754 (139 cases of bone) was expressed by two groups of MBD related gene chips. MM patients with qualitative damage) and GSE755 (34 patients without bone destruction) were used as research materials. Gene Spring GX11.5 software was used to carry out differential gene analysis on gene chip data. GATHER and other analysis tools annotate the possible molecular functions of MBD related differentially genes, various signaling pathways and pathways involved in the genetic analysis, and Cytosine software to analyze differential genes. The interaction relationship between encoding proteins. Results: a total of 173 samples were obtained from GSE754 and GSE755 gene chip data, and 435 differentially expressed genes were analyzed by Genesis software, of which 286 genes were expressed in high expression and 149 genes were low in expression. After introducing GATHER, these differentially expressed genes were found to increase mainly with cells. Colonization, calcium and phosphorus metabolism, cell cycle, cell adhesion and migration, cell apoptosis, proteasome, MAPK, chemokine signaling pathway, Erb B, cell cycle, cell deceleration and division, Wnt, T, B cell signaling pathways, JakSTAT, Rho A/ROCK and other signaling pathways. Analysis of differential genes into Cytosine software, and the results of proteins encoded by BMD related genes The interrelation between quality is mainly focused on NF- kappa B, PTK2B, ADD3, SPP1, IGF2, HSF2, HSF2, NTRK2, ADD3, GST6, CCL3, etc. Body, MAPK, Erb B, cell cycle, Wnt, Jak-STAT and other signaling pathways. The second part: screening and bioinformatics analysis of myeloma bone disease related genes and bioinformatics analysis: to be cultured in vitro by cell culture, exogenous to MIP-1 alpha and sclerostin, MIP-1 A and sclerostin McAbs to increase or neutralize myeloma cell strain RPMI-8226, H929 high expression sclerostin/MIP The level of -1 alpha and the level of sclerostin/MIP-1 alpha in the cell were observed. The correlation of the two proteins was preliminarily verified. Methods: the human myeloma cell line RPMI-8226, H929 was used as the research object. MIP-1 alpha and sclerostin protein levels in the cell supernatant were detected by ELISA. MIP-1 alpha and sclerostin M were detected by RT-PCR. RNA level. Results: after adding MIP-1 alpha in the two groups of cell supernatants for 24 hours, the level of MIP-1 alpha and sclerostin was significantly higher than that in the non intervention group (P value was 0). After adding MIP-1 a monoclonal antibody, the levels of MIP-1 alpha and sclerostin in the two groups were significantly lower than those in the non intervention group (P values were 0 and 0.001 respectively), and sclerostin and sclerostin were added. After mAb, the level of MIP-1 alpha in the two groups was not significantly higher than that in the non intervention group (P value was greater than 0.05). After adding sclerostin, the level of sclerostin in the two groups increased significantly (P value was less than 0.01), and the sclerostin level of the two groups was significantly decreased after adding sclerostin MAb (P value was less than 0.01). Conclusion: MIP-1 alpha mediates myeloma fine. Cell secretion of sclerostin, specific mechanisms need to be further studied. In conclusion, this study confirmed that sclerostin, MIP-1 alpha two proteins are highly expressed in most of MBD patients' bone marrow and myeloma cell lines, and are associated with tumor load, MBD classification, ISS staging, and a significant positive correlation. Information science related software and online tools further verified the association between sclerostin, MIP-1 alpha and two proteins. Through cell culture in vitro, MIP-1 alpha may promote tumor cells or bone marrow microenvironment to secrete sclerostin.. This reveals that the function of MIP-1 a in the suppression of OB in MBD may be through sclerostin The third part is to verify the relationship between MIP-1 and sclerostin in vitro.

【學(xué)位授予單位】：廣西醫(yī)科大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2016
【分類號(hào)】：R733.3

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