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》2016年博士論文

【摘要】：骨髓瘤骨病(MBD)是MM患者的最常見的并發(fā)癥之一。MBD發(fā)生的主要機制:在骨髓微環(huán)境中,瘤細胞與骨髓基質細胞(BMSCs)通過RANKL/RANK等經典途徑、巨噬細胞炎癥蛋白-1α(MIP-1α)等非經典途徑的信號通路,增強破骨細胞(OC)的數(shù)量、抑制成骨細胞(OB)的功能,最后導致溶骨性損害。本人前期研究及國內外最近研究報道MIP-1α不僅有增加OC的數(shù)量和增強OC的功能,還有抑制OB的分化和成熟,但抑制OB的具體機制不明。骨硬化蛋白(sclerostin)是SOST基因的表達產物,參與骨形成調節(jié),決定骨重建過程中的骨量和結構,是Wnt/β-信號通路的重要抑制劑,而Wnt/β-信號通路在介導OB分化、成熟及功能調節(jié)中是非常重要的。最近研究報道:MM患者外周血sclerostin增高,但其增多的機制以及與MM患者的生物學特征尚不明確。本研究試圖通過探討MBD患者骨髓血漿及骨髓瘤細胞株MIP-1α和sclerostin蛋白的表達,以此探明這兩種蛋白與患者的臨東快氮分期、生化特征、預后及兩者之間的關系等。通過從美國國立生物技術信息中心(GEO)的共享數(shù)據(jù)庫中下載MBD相關的基因芯片表達數(shù)據(jù)譜GSE754和GSE755,運用生物信息學相關工具進行數(shù)據(jù)和文獻挖掘,通過大數(shù)據(jù)分析MIP-1α和sclerostin蛋白是否具有一定的關聯(lián)性。進一步在體外驗證這兩種蛋白的相互關系,為MBD患者的防治開拓新思路和提供理論依據(jù)。本論文主要從如下三方面進行探討。第一部分MIP和sclerostin在骨髓瘤骨病患者中的表達及與臨東目的:本研究旨在探討MIP-1α和sclerostin在MBD中的表達,MIP-1α和sclerostin與MBD分級、ISS臨東及兩者相互之間的關系。方法:以53名MBD患者(其中女24名,男29名),人多發(fā)性骨髓瘤細胞株RPMI-8226、H929及30名白細胞減少癥、免疫性血小板減少癥患者為研究對象。酶聯(lián)免疫吸附法(ELISA)定量檢測骨髓血漿MIP-1α和sclerostin蛋白的水平;RT-PCR技術檢測MIP-1α和sclerostin蛋白的m RNA表達;電化學發(fā)光免疫法測量甲狀旁腺素(PTH)和1,25(OH)2Vit D3的水平,全自動生化分析儀檢測患者的各項常規(guī)生化指標等。實驗數(shù)據(jù)以均數(shù)±標準差表示,使用SPSS18.0統(tǒng)計學軟件進行分析。結果: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)蛋白濃度要高于對照組(t=6.85和8.26,p均為0.00)。體外骨髓瘤細胞株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的結果分析也證實了大部分的MBD患者骨髓單個核細胞(BMMNCs)及兩種骨髓瘤細胞株均表達這兩種蛋白,但表達的量不一致。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,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)之間呈負相關;sclerostin、MIP-1α蛋白的水平與MBD分級(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,高水平(0.54ng/ml)的sclerostin蛋白的MBD患者的中位生存時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患者的中位生存時間雖短于低水平的患者,但兩者比較無統(tǒng)計學差異(χ2=2.94,p=0.086)。雙重線性回歸結果提示ISS分期、sclerostin蛋白,β2-MG,MIP-1α蛋白是MBD分級獨立的預后不良因素。結論:1.MIP-1α、sclerostin在MBD患者骨髓中水平增高、骨髓瘤細胞系能分泌這兩種蛋白,但不同細胞系表達水平不一定相同;2.MIP-1α、sclerostin與臨床ISS分期、MBD分級、與反應瘤負荷的相關指標β2-MG、LDH水平呈正相關,而與b ALP、HB、ALB則呈負相關。3.高水平(0.54ng/ml)的sclerostin的MBD患者的中位生存時間要短于低水平的MBD患者.4.MIP-1α與sclerostin呈明顯的正相關。目的:采用生物信息學各種軟件和在線工具進行篩選MBD的相關基因,并對其進行數(shù)據(jù)和文獻挖掘,進一步通過大數(shù)據(jù)了解MIP-1α與sclerostin是否具有一定的關聯(lián)性。方法:以MBD相關的兩組患者基因芯片表達數(shù)據(jù)譜GSE754(139例有骨質破壞的MM患者)和GSE755(34例無骨質破壞的患者)為研究材料,運用Gene Spring GX11.5軟件對基因芯片數(shù)據(jù)進行差異基因分析,GATHER等分析工具注釋MBD相關差異基因可能的分子功能、參與的各種信號通路及通路富集,Cytosine軟件分析差異基因編碼蛋白質之間的相互作用關系。結果:從GSE754和GSE755基因芯片數(shù)據(jù)中分析得到共173個樣本,經Genesis軟件分析得出435個共同表達的差異基因,其中高表達的有286個基因,低表達的有149個基因。導入GATHER后發(fā)現(xiàn)這些差異基因主要與細胞增殖、鈣磷代謝、細胞周期,細胞粘附與遷移、細胞凋亡、蛋白酶體、MAPK、趨化因子信號通路、Erb B、細胞周期,細胞減速分裂、Wnt、T、B細胞信號通路、JakSTAT、Rho A/ROCK等信號通路有關。將差異基因導入Cytosine軟件中分析,結果發(fā)現(xiàn)BMD相關基因編碼的蛋白質間的相互聯(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。結論:通過對基因芯片大數(shù)據(jù)進行生物信息學相關分析篩選得出MIP-1α與sclerostin具有一定的關聯(lián)性,參與MBD的發(fā)生主要涉及到蛋白酶體、MAPK、Erb B、細胞周期,Wnt、Jak-STAT等信號通路。第二部分:骨髓瘤骨病相關基因的篩選及生物信息學分析目的:擬在體外通過細胞培養(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胞株RPMI-8226、H929高表達sclerostin/MIP-1α的水平,觀察該細胞的sclerostin/MIP-1α的水平變化。初步驗證這兩種蛋白的關聯(lián)性。方法:以人骨髓瘤細胞系RPMI-8226、H929為研究對象,ELISA定量檢測各組細胞上清液中的MIP-1α和sclerostin蛋白水平,RT-PCR定量檢測各組細胞的MIP-1α和sclerostin m RNA水平。結果:兩組細胞上清液中加入MIP-1α后再培養(yǎng)24小時,MIP-1α和sclerostin水平較不干預組明顯增高(p值均為0.00);加入MIP-1α單抗后,兩組細胞中的MIP-1α和sclerostin水平較不干預組明顯下降(p值分別為0.00和0.001);加入sclerostin及sclerostin單抗后,兩組細胞的MIP-1α水平較不干預組改變不明顯(p值均大于0.05),加入sclerostin后,兩組細胞的sclerostin水平明顯增高(p值均小于0.01),而加入sclerostin單抗后,兩組細胞的sclerostin水平明顯下降(p值均小于0.01)。結論:MIP-1α可介導骨髓瘤細胞分泌sclerostin,具體機制需進一步研究。總之,本研究驗證了sclerostin、MIP-1α兩種蛋白在大部分MBD患者骨髓中及骨髓瘤細胞株中呈高表達,且與瘤負荷、MBD分級、ISS分期相關,兩種蛋白呈明顯的正相關。通過從GEO下載基因芯片大數(shù)據(jù),運用生物信息學相關軟件和在線工具進一步驗證了sclerostin、MIP-1α兩種蛋白有一定的關聯(lián)。在體外通過細胞培養(yǎng)技術驗證了MIP-1α可能通過各種途徑促進瘤細胞或骨髓微環(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sclerostin來介導的可能機制。第三部分體外通過細胞培養(yǎng)驗證MIP-1α和sclerostin的關系
[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.

【學位授予單位】：廣西醫(yī)科大學
【學位級別】：博士
【學位授予年份】：2016
【分類號】：R733.3

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