本文選題：骨礦化異常 + 胎球蛋白A-基質(zhì)gla蛋白-鈣磷礦化復(fù)合物　； 參考：《湖北中醫(yī)藥大學(xué)》2016年博士論文

【摘要】：目的從理論研究的角度總結(jié)絕經(jīng)后骨質(zhì)疏松癥(PMOP)的發(fā)病機(jī)制,從臨床研究的角度探索PMOP患者基質(zhì)gla蛋白(MGP)與骨代謝的關(guān)系及胎球蛋白A-基質(zhì)gla蛋白-鈣磷礦化復(fù)合物(FMC)參與PMOP的發(fā)病機(jī)制,并觀察中藥淫羊藿膠囊治療PMOP患者(腎陽虧虛證)的臨床療效和作用機(jī)制。方法1、理論研究:查閱文獻(xiàn),總結(jié)PMOP的發(fā)病機(jī)制,分析骨礦化異常與PMOP之間的關(guān)系;對古今相關(guān)文獻(xiàn)進(jìn)行系統(tǒng)的回顧總結(jié),以了解中醫(yī)對PMOP的病因病機(jī)及治則治法的認(rèn)識,為臨床試驗研究提供理論依據(jù)。2、血清基質(zhì)gla蛋白與骨代謝的相關(guān)性:本研究錄入120例PMOP患者和60例骨量正常的絕經(jīng)后婦女。通過聚合酶鏈?zhǔn)椒磻?yīng)(PCR)檢測血清MGP m RNA水平,骨狀態(tài)通過骨密度(BMD)和骨轉(zhuǎn)換標(biāo)志物(β-CTX,P1NP)評估。此外,也檢測血清雌二醇(E2)、甲狀旁腺素(PTH)、血鈣(Ca)、血磷(P)水平。3、胎球蛋白A-基質(zhì)gla蛋白-鈣磷復(fù)合體(FMC)參與PMOP的機(jī)制研究:選取行腰椎手術(shù)的PMOP患者和骨量正常的絕經(jīng)后女性各23例,在手術(shù)時取其部分腰椎骨組織,患者血清胎球蛋白A(fetuin A)、基質(zhì)gla蛋白(MGP)、骨形態(tài)發(fā)生蛋白2(BMP2)、runt相關(guān)轉(zhuǎn)錄因子2(RUNX2)水平采用酶聯(lián)免疫吸附法(ELISA)檢測,骨組織局部fetuin A、MGP、BMP2、RUNX2 m RNA及蛋白的表達(dá)則分別通過PCR及免疫組化的方法檢測。4、中藥療效研究:選取PMOP患者90例,將其隨機(jī)雙盲分為A組(安慰劑對照組)、B組(淫羊藿膠囊低劑量組)及C組(淫羊藿膠囊高劑量組),共治療24周。于治療前和治療24周后,觀測患者疼痛VAS評分、主要癥候評分、中醫(yī)證候積分療效變化,并檢測患者BMD、血清中PINP、β-CTX及血清Fetuin-A、MGP水平的變化。統(tǒng)計學(xué)的處理:數(shù)據(jù)的分析處理采用統(tǒng)計軟件SPSS 20.0進(jìn)行,所有的數(shù)據(jù)都用均數(shù)±標(biāo)準(zhǔn)差(x±s)的形式表示,統(tǒng)計結(jié)果出現(xiàn)P0.05則認(rèn)為差異具有統(tǒng)計學(xué)的意義。結(jié)果1、查閱文獻(xiàn),研究表明骨礦化異常是OP/PMOP的發(fā)病原因之一,FMC的形成是維持正常骨礦化的重要機(jī)制,但FMC是如何參與OP/PMOP發(fā)病的尚不清楚;中醫(yī)學(xué)認(rèn)為OP/PMOP的發(fā)病關(guān)鍵在于多種原因?qū)е碌哪I虛髓虧,還與脾胃虛弱、肝血不足、瘀血阻滯有關(guān)。此外,我的導(dǎo)師向楠教授痰濁也是OP發(fā)病的重要因素。因此中醫(yī)藥治療OP/PMOP也以補(bǔ)腎為基礎(chǔ),補(bǔ)腎中藥是否能夠通過影響骨礦化從而改善OP/PMOP的臨床癥狀有待研究。2、PMOP組與非骨質(zhì)疏松組相比,BMD、MGP m RNA、β-CTX、P1NP的差異有統(tǒng)計學(xué)意義(P0.05)。PMOP患者血清MGP m RNA水平顯著低于對照組(0.835±0.415 VS 4.524±0.769,P0.001),與BMD(r=0.376,P0.001)、E2(r=0.227,P=0.013)呈正相關(guān)。未發(fā)現(xiàn)MGPm RNA與年齡、身高、體重、PTH、Ca、P、β-CTX,P1NP有明顯相關(guān)性。在骨量正常的絕經(jīng)后婦女中,在MGP m RNA與其他參數(shù)之間沒有發(fā)現(xiàn)明顯的相關(guān)性。3、PMOP組血清Fetuin-A、MGP、腰椎BMP2、Runx2 m RNA表達(dá)明顯低于非骨質(zhì)疏松組,而腰椎MGPm RNA表達(dá)高于非骨質(zhì)疏松組(P0.05);兩組間比較,血清BMP2、RUNX2水平、腰椎Fetuin-A m RNA表達(dá)沒有明顯的差異(P0.05)。多元邏輯回歸分析顯示,腰椎MGP、BMP2及RUNX2 m RNA表達(dá)與BMD相關(guān)(分別是OR 1.016,95%CI0.809-0.991,P=0.029;OR1.230,95%CI1.063-1.424,P=0.015;OR 1.107,95%CI1.016-1.205,P=0.048)。免疫組織化學(xué)結(jié)果顯示,骨小梁周邊的成骨細(xì)胞及骨髓基質(zhì)細(xì)胞胞漿均可見Fetuin-A、BMP2、RUNX2、MGP的陽性表達(dá),骨小梁周邊的破骨細(xì)胞還可見到MGP的陽性表達(dá)。與非骨質(zhì)疏松組相比,PMOP組MGP的光密度值水平較高(P0.05)而BMP2和RUNX2水平較低(P0.05或P0.01);兩組間比較,Fetuin-A光密度值水平差異不明顯(P0.05);4、同治療前相對比,B、C兩組都能有效改善患者的臨床癥狀、增加患者腰椎及股骨頸的骨密度、提高血清Fetuin-A及MGP的水平(P0.05),對骨代謝標(biāo)志物影響不明顯(P0.05);其中C組能更快緩解疼痛,且對腰椎骨密度的升高效果更為顯著(P0.01)。與治療前比較,A組對各項指標(biāo)影響均不顯著(P0.05)。結(jié)論1、臨床與試驗研究提示,MGP與PMOP有一定的相關(guān)性,而FMC很可能通過影響骨礦化從而影響PMOP的發(fā)病;補(bǔ)腎中藥治療PMOP有中醫(yī)的理論基礎(chǔ),也有現(xiàn)代試驗研究的支持。2、低血清MGP m RNA水平可能與PMOP的發(fā)病有關(guān),而雌激素參與對血清MGP的調(diào)控。3、血清FMC的合成減少及MGP在局部骨組織聚集,可能通過影響B(tài)MP2/Smad/Runx2信號通路,抑制正常的骨礦化,從而影響PMOP的發(fā)生。4、中藥淫羊藿能夠改善PMOP腎陽虧虛證患者的臨床癥狀,增加BMD,并且其效果跟用藥劑量呈相關(guān),其作用機(jī)制可能與增加血清FMC的合成有關(guān)。
[Abstract]:Objective to summarize the pathogenesis of postmenopausal osteoporosis (PMOP) from a theoretical point of view, and to explore the relationship between matrix Gla protein (MGP) and bone metabolism in PMOP patients and A- matrix Gla protein calcium phosphate mineralization complex (FMC) involved in the pathogenesis of PMOP from the perspective of clinical research, and to observe the treatment of PMOP patients (kidneys) with Epimedium capsule (Epimedium capsule). The clinical curative effect and mechanism of action of Yang deficiency syndrome). Method 1, theoretical study: consult the literature, summarize the pathogenesis of PMOP, analyze the relationship between the abnormal bone mineralization and the PMOP, review the relevant literature of ancient and modern, in order to understand the understanding of the etiology, pathogenesis and treatment of PMOP, and provide the theoretical basis for the clinical trial. 2, the correlation between serum matrix Gla protein and bone metabolism: This study entered 120 patients with PMOP and 60 postmenopausal women with normal bone mass. The serum MGP m RNA level was detected by polymerase chain reaction (PCR), bone state was evaluated by bone density (BMD) and bone conversion markers (beta -CTX, P1NP). Serum estradiol (E2), parathyroid hormone was also detected. (PTH) the mechanism of blood calcium (Ca), blood phosphorus (P) level.3, fetal globulin A- matrix Gla protein calcium phosphate complex (FMC) involved in PMOP: 23 cases of PMOP patients and postmenopausal women with normal bone mass were selected for the operation of lumbar vertebrae, and some of the lumbar vertebrae were taken during the operation, and the serum fetal globulin A (fetuin A), matrix protein, and bone morphogenesis Protein 2 (BMP2), runt related transcription factor 2 (RUNX2) level was detected by enzyme linked immunosorbent assay (ELISA). The local fetuin A, MGP, BMP2, RUNX2 m RNA and protein expression were detected by PCR and immunohistochemical methods respectively. 90 patients were selected and randomly divided into placebo control group (placebo control group). The low dose group of Epimedium capsule and C group (high dose group of Epimedium capsule) were treated for 24 weeks. Before and after 24 weeks of treatment, the pain VAS score, main syndrome score, TCM syndrome integral effect change, and the changes of BMD, serum PINP, beta -CTX and serum Fetuin-A, MGP level were detected. Statistical analysis: data analysis The treatment was carried out using the statistical software SPSS 20. All the data were expressed in the form of mean mean standard deviation (x + s). The statistical results showed that the difference was statistically significant. Results 1. The results showed that the abnormal bone mineralization was one of the causes of OP/PMOP, and the formation of FMC was an important mechanism for maintaining normal bone mineralization, but F It is not clear how MC participates in the pathogenesis of OP/PMOP; traditional Chinese medicine believes that the key to the pathogenesis of OP/PMOP lies in the deficiency of kidney marrow caused by many reasons, and it is related to weakness of the spleen and stomach, insufficiency of liver blood and stasis of blood. In addition, my tutor, professor Xiang Nan, is also an important factor in the pathogenesis of OP. In this case, OP/PMOP is also based on kidney tonifying and kidney tonifying. The difference in BMD, MGP m RNA, beta -CTX, P1NP (P0.05).PMOP patients was significantly lower than that of the control group (P0.05).PMOP patients (0.835 + 0.415, 4.524 + 0.769, PMOP). R=0.227, P=0.013) was positively correlated. No MGPm RNA was found to be associated with age, height, weight, PTH, Ca, P, and beta -CTX, and P1NP had a significant correlation. The expression of MGPm RNA in the lumbar spine was higher than that in the non osteoporosis group (P0.05), and there was no significant difference between the two groups, the serum BMP2, the RUNX2 level, and the Fetuin-A m RNA expression (P0.05). 015; OR 1.107,95%CI1.016-1.205, P=0.048). The immunohistochemical results showed that the cytoplasm of osteoblasts and bone marrow stromal cells around the bone trabeculae showed Fetuin-A, BMP2, RUNX2, MGP positive expression, and the positive expression of MGP in the osteoclasts around the trabecular bone. Compared with the non osteoporotic group, the optical density of MGP in the PMOP group was more than that of the non osteoporotic group. High (P0.05) and BMP2 and RUNX2 levels were lower (P0.05 or P0.01); compared with the two groups, the difference of Fetuin-A light density level was not obvious (P0.05); 4, compared with before treatment, B, C two groups could effectively improve the patient's clinical symptoms, increase the bone density of the lumbar and femoral neck, increase the level of serum Fetuin-A and MGP (P0.05), and bone metabolic markers. The effect was not obvious (P0.05), of which group C could relieve pain faster and increase the effect of lumbar bone density more significantly (P0.01). Compared with before treatment, group A had no significant influence on various indexes (P0.05). Conclusion 1, clinical and experimental studies suggest that MGP has a certain correlation with PMOP, and FMC is likely to affect PMOP by affecting bone mineralization. The treatment of PMOP has the theoretical basis of traditional Chinese medicine and the support of modern experimental research. The level of the low serum MGP m RNA may be related to the pathogenesis of PMOP, while estrogen participates in the regulation of the serum MGP, the decrease of serum FMC and the accumulation of MGP in the local bone tissue can affect the BMP2/Smad/Runx2 signaling pathway and inhibit normal. Bone mineralization affects the occurrence of.4 in PMOP. The Chinese herb Epimedium can improve the clinical symptoms of the patients with PMOP deficiency syndrome and increase the BMD, and the effect is related to the dosage of the drug. The mechanism of its action may be related to the increase of the synthesis of serum FMC.

【學(xué)位授予單位】：湖北中醫(yī)藥大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2016
【分類號】：R259

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