本文選題：肥大性骨關(guān)節(jié)病 + 骨硬素�。� 參考：《北京協(xié)和醫(yī)學(xué)院》2015年博士論文

【摘要】：背景原發(fā)性肥大性骨關(guān)節(jié)病(primary hypertrophic osteoarthropathy,PHO)是一類罕見的遺傳性疾病,以杵狀指、皮膚增厚和長骨骨膜增生為特征。目前發(fā)現(xiàn)2個基因和該病相關(guān)：15-羥前列腺素脫氫酶基因(HPGD)突變導(dǎo)致PHO常染色隱性1型(PHOAR1),陰離子轉(zhuǎn)運(yùn)蛋白家族2A1(SLCO2A1)突變導(dǎo)致PHO常染色體隱性2型(PHOAR2),兩種基因突變均導(dǎo)致體內(nèi)前列腺素E2(prostaglandin E2,PGE2)代謝障礙,但兩種PHO亞型在臨床表現(xiàn)上有所差異。Wingless-type(Wnt)通路是骨代謝的重要通路,其抑制劑slcerostin和Dickkopf家族可能在PHO的發(fā)病過程中發(fā)揮作用。環(huán)氧化酶-2(COX-2)抑制劑可以降低PGE2水平,是針對性治療PHO的有效藥物之一,但目前缺乏對其療效和不良反應(yīng)的長期隨訪以及系統(tǒng)性評估。目的1、對本院就診的27例原發(fā)性肥大性骨關(guān)節(jié)病患者的臨床特點(diǎn)進(jìn)行分析總結(jié)；2、對兩種不同突變的原發(fā)性肥大性骨關(guān)節(jié)病亞型進(jìn)行比較,分析其差異原因；3、測定原發(fā)性肥大性骨關(guān)節(jié)病患者體內(nèi)Wnt信號通路相關(guān)蛋白水平,探究Wnt通路在原發(fā)性肥大性骨關(guān)節(jié)病發(fā)病機(jī)制中的作用；4、觀察COX-2抑制劑對于原發(fā)性肥大性骨關(guān)節(jié)病的治療效果及不良反應(yīng)。對象和方法1、研究對象：北京協(xié)和醫(yī)院收治的27例原發(fā)性肥大性骨關(guān)節(jié)病患者2、研究方法：(1)對27例原發(fā)性肥大性骨關(guān)節(jié)病患者進(jìn)行臨床特征總結(jié);(2)基因突變分析：對患者的DNA樣品針對致病基因HPGD、SLCO2A1進(jìn)行PCR擴(kuò)增及測序,比較不同突變亞型患者的臨床特征；(3)Wnt信號通路相關(guān)蛋白水平測定：對患者的血標(biāo)本通過ELISA進(jìn)行sclerostin、 Dkk-1的檢測,比較其和正常對照的差異及治療前后的變化；(4)COX-2抑制劑治療隨訪：對入組的原發(fā)性肥大性骨關(guān)節(jié)病患者予安康信60mg每日一次治療,觀察用藥0、1、3、6、12個月臨床及實(shí)驗室指標(biāo)變化以及不良事件發(fā)生。結(jié)果1 總結(jié)27例原發(fā)性肥大性骨關(guān)節(jié)病患者特征,主要臨床癥狀為杵狀指、皮膚增厚、骨膜增生三聯(lián)征,掌跖多汗、關(guān)節(jié)腫痛亦較為常見,主要并發(fā)癥包括腹瀉、貧血。生化方面,該病表現(xiàn)為炎性指標(biāo)增高,血清及尿PGE2增高。影像學(xué)方面,長骨、指骨骨皮質(zhì)增厚及肢端骨溶解為典型特征。2本研究發(fā)現(xiàn)HPGD突變患者7例,SLCO2A1突變患者20例,其性別比、起病年齡、肢端骨溶解程度、血清及尿PGEM水平、并發(fā)癥均有所不同。3 原發(fā)性肥大性骨關(guān)節(jié)病患者sclerostin與正常人無顯著差異,但COX-2抑制劑治療后水平顯著增高；Dkk-1低于正常對照,在COX-2抑制劑治療后先降低、后升高。4選擇性COX-2抑制劑可以有效改善原發(fā)性肥大性骨關(guān)節(jié)病的杵狀指、面部皮膚增厚、關(guān)節(jié)腫痛癥狀,降低其炎癥指標(biāo)及體內(nèi)PGE2水平,不良反應(yīng)少,但停藥后可出現(xiàn)癥狀反復(fù)。結(jié)論1、總結(jié)了國內(nèi)最大樣本原發(fā)性肥大性骨關(guān)節(jié)病患者的臨床資料。2、對兩種不同突變亞型的原發(fā)性肥大性骨關(guān)節(jié)病進(jìn)行比較,提示其臨床及生化特征存在顯著差異,可能和兩種突變機(jī)制不同有關(guān)。3、原發(fā)性肥大性骨關(guān)節(jié)病患者Wnt信號通路相關(guān)蛋白水平異常,提示W(wǎng)nt通路和原發(fā)性肥大性骨關(guān)節(jié)病發(fā)病機(jī)制相關(guān)。4、選擇性COX-2抑制劑對于原發(fā)性肥大性骨關(guān)節(jié)病治療效果明確。
[Abstract]:Background : Primary hypertrophic osteoarticular disease ( PHO ) is a rare hereditary disease characterized by a clubbing finger , thickening of skin and osteoproliferation of long bone . The mutation of the 15 - hydroxyprostaglandin dehydrogenase gene ( HPGD ) leads to a recessive type 1 of PHO .
2 . To compare the subtype of primary hypertrophic osteoarticular disease with two different mutations , and analyze its causes .
3 . To determine the level of Wnt signaling pathway in patients with primary hypertrophic osteoarticular disease and investigate the role of Wnt pathway in the pathogenesis of primary hypertrophic osteoarthrosis .
4 . To observe the therapeutic effect and adverse reaction of COX - 2 inhibitor on primary hypertrophic osteoarticular diseases . The object and method 1 , research object : 27 cases of primary hypertrophic osteoarticular disease treated by Peking Union and Hospital : ( 1 ) The clinical characteristics of 27 patients with primary hypertrophic osteoarticular disease were summarized ; ( 2 ) gene mutation analysis : PCR amplification and sequencing of DNA samples of patients were carried out against pathogenic genes HPGD and SLCO2A1 , and the clinical characteristics of patients with different mutation subtypes were compared ;
( 3 ) Measurement of the protein level of Wnt signaling pathway : the serum samples of patients were detected by ELISA for the detection of sclerostin and D98- 1 , and the differences between them were compared with those of the normal controls and the changes before and after treatment .
( 4 ) Follow - up of COX - 2 inhibitor : A total of 27 patients with primary hypertrophic osteoarticular disease were treated daily for 0 , 1 , 3 , 6 , 12 months in clinical and laboratory indexes and adverse events . Results 1 A total of 27 patients with primary hypertrophic osteoarticular diseases were observed .
Conclusion 1 . The clinical data of the patients with primary hypertrophic osteoarticular disease can be improved by selective COX - 2 inhibitor . Conclusion 1 . It is suggested that the clinical and biochemical characteristics of patients with primary hypertrophic osteoarticular disease are different .
【學(xué)位授予單位】：北京協(xié)和醫(yī)學(xué)院
【學(xué)位級別】：博士
【學(xué)位授予年份】：2015
【分類號】：R684

【共引文獻(xiàn)】

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本文編號：1949843