原发性肥大性骨关节病Wnt通路相关因子水平和COX-2抑制剂干预后的变化

发布时间：2018-05-29 06:28

本文选题：肥大性骨关节病 + 骨硬素　；参考：《北京协和医学院》2015年博士论文

【摘要】：背景原发性肥大性骨关节病(primary hypertrophic osteoarthropathy,PHO)是一类罕见的遗传性疾病,以杵状指、皮肤增厚和长骨骨膜增生为特征。目前发现2个基因和该病相关：15-羟前列腺素脱氢酶基因(HPGD)突变导致PHO常染色隐性1型(PHOAR1),阴离子转运蛋白家族2A1(SLCO2A1)突变导致PHO常染色体隐性2型(PHOAR2),两种基因突变均导致体内前列腺素E2(prostaglandin E2,PGE2)代谢障碍,但两种PHO亚型在临床表现上有所差异。Wingless-type(Wnt)通路是骨代谢的重要通路,其抑制剂slcerostin和Dickkopf家族可能在PHO的发病过程中发挥作用。环氧化酶-2(COX-2)抑制剂可以降低PGE2水平,是针对性治疗PHO的有效药物之一,但目前缺乏对其疗效和不良反应的长期随访以及系统性评估。目的1、对本院就诊的27例原发性肥大性骨关节病患者的临床特点进行分析总结；2、对两种不同突变的原发性肥大性骨关节病亚型进行比较,分析其差异原因；3、测定原发性肥大性骨关节病患者体内Wnt信号通路相关蛋白水平,探究Wnt通路在原发性肥大性骨关节病发病机制中的作用；4、观察COX-2抑制剂对于原发性肥大性骨关节病的治疗效果及不良反应。对象和方法1、研究对象：北京协和医院收治的27例原发性肥大性骨关节病患者2、研究方法：(1)对27例原发性肥大性骨关节病患者进行临床特征总结;(2)基因突变分析：对患者的DNA样品针对致病基因HPGD、SLCO2A1进行PCR扩增及测序,比较不同突变亚型患者的临床特征；(3)Wnt信号通路相关蛋白水平测定：对患者的血标本通过ELISA进行sclerostin、 Dkk-1的检测,比较其和正常对照的差异及治疗前后的变化；(4)COX-2抑制剂治疗随访：对入组的原发性肥大性骨关节病患者予安康信60mg每日一次治疗,观察用药0、1、3、6、12个月临床及实验室指标变化以及不良事件发生。结果1 总结27例原发性肥大性骨关节病患者特征,主要临床症状为杵状指、皮肤增厚、骨膜增生三联征,掌跖多汗、关节肿痛亦较为常见,主要并发症包括腹泻、贫血。生化方面,该病表现为炎性指标增高,血清及尿PGE2增高。影像学方面,长骨、指骨骨皮质增厚及肢端骨溶解为典型特征。2本研究发现HPGD突变患者7例,SLCO2A1突变患者20例,其性别比、起病年龄、肢端骨溶解程度、血清及尿PGEM水平、并发症均有所不同。3 原发性肥大性骨关节病患者sclerostin与正常人无显著差异,但COX-2抑制剂治疗后水平显著增高；Dkk-1低于正常对照,在COX-2抑制剂治疗后先降低、后升高。4选择性COX-2抑制剂可以有效改善原发性肥大性骨关节病的杵状指、面部皮肤增厚、关节肿痛症状,降低其炎症指标及体内PGE2水平,不良反应少,但停药后可出现症状反复。结论1、总结了国内最大样本原发性肥大性骨关节病患者的临床资料。2、对两种不同突变亚型的原发性肥大性骨关节病进行比较,提示其临床及生化特征存在显著差异,可能和两种突变机制不同有关。3、原发性肥大性骨关节病患者Wnt信号通路相关蛋白水平异常,提示Wnt通路和原发性肥大性骨关节病发病机制相关。4、选择性COX-2抑制剂对于原发性肥大性骨关节病治疗效果明确。
[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 .
【学位授予单位】：北京协和医学院
【学位级别】：博士
【学位授予年份】：2015
【分类号】：R684

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