关键词： microarray   heart valve maturation   asporin   osteoglycin   Twist1   collagen  

摘要： Chakraborty S, Cheek J, Sakthivel B, Aronow BJ, Yutzey KE. Shared gene expression profiles in developing heart valves and osteoblast progenitor cells. Physiol Genomics 35: 75-85, 2008. First published July 8, 2008;doi: 10.1152/physiolgenomics.90212.2008.-The atrioventricular (AV) valves of the heart develop from undifferentiated mesenchymal endocardial cushions, which later mature into stratified valves with diversified extracellular matrix (ECM). Because the mature valves express genes associated with osteogenesis and exhibit disease-associated calcification, we hypothesized the existence of shared regulatory pathways active in developing AV valves and in bone progenitor cells. To define gene regulatory programs of valvulogenesis relative to osteoblast progenitors, we undertook Affymetrix gene expression profiling analysis of murine embryonic day (E)12.5 AV endocardial cushions compared with E17.5 AV valves (mitral and tricuspid) and with preosteoblast MC3T3-E1 (subclone4) cells. Overall, MC3T3 cells were significantly more similar to E17.5 valves than to E12.5 cushions, supporting the hypothesis that valve maturation involves the expression of many genes also expressed in osteoblasts. Several transcription factors characteristic of mesenchymal and osteoblast precursor cells, including Twist1, are predominant in E12.5 cushion. Valve maturation is characterized by differential regulation of matrix metalloproteinases and their inhibitors as well as complex collagen gene expression. Among the most highly enriched genes during valvulogenesis were members of the small leucine-rich proteoglycan (SLRP) family including Asporin, a known negative regulator of osteoblast differentiation and mineralization. Together, these data support shared gene expression profiles of the developing valves and osteoblast bone precursor cells in normal valve development and homeostasis with potential functions in calcific valve disease.

关键词： LMP-1基因   椎间盘退变   基因治疗  

摘要： 细胞内信号转导分子LIM矿化蛋白-1(LMP-1)基因是近年证实与椎间盘退变相关的基因之一,其表达产物为一种细胞内非分泌性骨诱导蛋白。它可通过调节各种细胞因子的生成和其他相关基因的表达,来实现其所诱导的透明样基质的合成增加。研究证明LMP-1基因在椎间盘细胞过度表达,以及通过骨形态发生蛋白介导机制,在体内外条件下均可增加蛋白聚糖、硫酸氨基葡聚糖及Ⅱ型胶原的合成,从而减缓甚至逆转椎间盘细胞的退化。

关键词： PLAP-1   asporin   SLRP   BMP-2   Smad   leucine-rich repeat  

摘要： We previously identified the novel gene, periodontal ligament-associated protein-1 (PLAP-1)/asporin and reported that PLAP-1/asporin inhibited bone morphogenetic protein-2 (BMP-2)-induced cytodifferentiation of periodontal ligament (PDL) cells probably by direct interaction with BMP-2. Here, we elucidated the detailed regulatory mechanism of this protein on BMP-2-induced cytodifferentiation of PDL cells. Recombinant PLAP-1 /asporin inhibited BMP-2-induced cytodifferentiation of PDL cells and competitively prevented BMP-2 from binding to the BMP receptor-IB (BMPR-IB), resulting in inhibition of BMP-dependent activation of Smad proteins. The induction of mutation to the leucine-rich repeat (LRR) motif, especially LRR5, within PLAP-1 /asporin rescued the inhibitory effect of PLAP-I /asporin on BMP-2. By contrast, a 26-amino acid peptide in the PLAP-1/asporin LRR5 sequence inhibited BMP-2 activity. Our findings indicate that PLAP-1 /asporin inhibits BMP-2-induced differentiation of PDL cells resulting from inactivation of the BMP-2 signaling pathway and that LRR, especially LRR5 of PLAP-1 /asporin, plays an important role in the PLAP-1/asporin-BMP-2 interaction. (C) 2008 Elsevier Inc. All rights reserved.

关键词： Asporin   osteoarthritis   polymorphism   susceptibility   Korean population  

摘要： Osteoarthritis (OA) is a common disease that is characterized by the degeneration of joint cartilage in the knee, hip and hand. Recently, it has been reported that susceptibility to OA is affected by the number of aspartic acid (D) residues in the amino-terminal of the asporin protein. In order to investigate whether the association found in Japanese OA is also present in the Korean population, the frequency of the polymorphism was examined in 190 OA patients and 376 healthy controls. The D-repeat microsatellite polymorphism was examined by amplifying the asporin gene and sequencing its products. The frequencies of the D13 and D14 alleles were 69.7% (265/380) and 5.8% (22/380), respectively, in OA patients and 64.2% (483/752) and 8.7% (65/752), respectively, in healthy controls. When we adjusted for gender and age, there was no statistically significant difference between Korean OA patients and healthy controls (P =0.1082) in the allele frequency of D13 compared to the other alleles. However, a significant difference between female OA patients and their controls (P=0.0245) in the allele frequency of the D13 allele was found compared to the other alleles. There was no significant difference between Korean OA patients and healthy controls in the frequency of the D14 and other alleles (P=0.2339). These results suggest that asporin may play a role in OA susceptibility of the knee in the Korean female population. (C) 2007 Elsevier B.V. All rights reserved.

关键词： asporin基因   微卫星多态性   骨性关节炎   中国汉族   病例对照  

摘要： 目的研究中国汉族人群天门冬氨酸（D）重复序列多态性与膝骨性关节炎（OA）关系。方法对218例具有原发症状并有影象学证据的膝OA患者以及454名年龄相匹配的对照组进行D重复序列多态性的基因型测定,并检测重复序列的等位基因之间关系。结果D13和D14等位基因频率与日本人群相似,而与欧洲高加索人群不同。D14等位基因在膝OA患者中显著表达（P=0.0013;OR=2.04;95%CI=1.32-3.15）。早发的膝OA患者D14频率要高于迟发的患者（P=0.043）,并且带有D14等位基因患者的发病年龄要早于无D14的患者（P=0.028;log-rank时序检验）。结论中国汉群人群D14等位基因与膝OA易感性呈著相关。

关键词： 椎间盘退变性疾病   基因治疗   Sox9   颈肩腰腿疼痛   临床症状   主要表现   住院人数   药物治疗  

摘要： 椎间盘退变性疾病(disc degeneration disease,DDD)是一种发病率及致残率极高的疾病,常引起以颈肩腰腿疼痛为主要表现的临床症候群,据资料表明,DDD患者占美国骨科住院人数的1/3以上,目前对DDD的常规治疗方法包括药物治疗、理疗、卧床休息、类固醇注射封闭以及手术治疗等。但是,这些措施仅能够改善疾病的临床症状,并不能从根本上减缓或终止退变的进程。[第一段]

关键词： MONOGENIC & polygenic inheritance (Genetics)   EXTRACELLULAR matrix proteins   OSTEOARTHRITIS   GENES   ASIANS  

摘要： Lumbar-disc degeneration (LDD) is a polygenic disease. Susceptibility genes reported so far are mainly extracellular matrix proteins. D14 allele of asporin (ASPN) is associated with osteoarthritis (OA). Candidate-gene association studies showed that the D14 allele is also significantly associated with LDD in Chinese and Japanese individuals. Meta-analysis showed that individuals harboring a D14 allele had higher risk with a summary odds ratio of 1.70 (p = 0.000013). ASPN expression in vertebral discs increased with age and degeneration. Our results indicate ASPN is a LDD gene in Asians, and common risk factors may be considered for OA and LDD.

关键词： asporin基因   微卫星多态性   骨性关节炎   中国汉人   病例对照  

摘要： 目的 评估在中国汉族人群中天门冬氨酸(D)重复序列多态性与膝OA是否相关。 方法 对218名具有原发症状并有影象学证据的膝骨性关节炎(OA)患者以及454名年龄相匹配的对照组进行D重复序列多态性的基因型测定,并检测重复序列的等位基因之间关系。 结果 D13和D14等位基因频率与日本人群相似,而与欧洲高加索人群不符。D14等位基因在膝OA患者中显著表达(P=0.0013;OR=2.04:95%CI 1.32-3.15)。早发的膝OA患者的D14频率要高于迟发的患者(P=0.043),并且带有D14等位基因的患者的发病年龄要早于无D14的患者(P=0.028;log-rank时序检验)。 结论在中国汉族人群中D14等位基因与膝OA易感性呈显著相关。

关键词： 脊柱炎，强直性   程序性死亡基因   PD-L1   PD-L2   Asporin   多态现象(遗传学)   全基因组扫描   肿瘤坏死因子   Meta分析  

摘要： 目的:探讨程序性细胞死亡基因(PD-1)及其配体PD-L1、PD-L2的单核苷酸多态性(SNP)对山东汉族人群强直性脊柱炎(AS)患者易感性的影响;分析Asporin(ASPN)基因天冬氨酸(D)重复多态性与AS的关联;评估AS全基因组扫描研究结果,进一步确定AS遗传易感基因的染色体区域定位;探讨AS与肿瘤坏死因子α基因启动子—308位点多态性的关联情况。 方法:1、收集2006年1月至2007年10月在山东省立医院就诊的AS患者196例和180例正常对照,采用PCR-RELP和real time PCR熔解曲线方法,分析PD-1rs2227981、PD-1rs2227982及配体PD-L1 rs822336、PD—L2 rs6476985、PD—L2rs1009759等在AS和正常对照人群的分布情况,基因测序鉴定SNP分型结果。结合AS患者临床表型进行统计学分析。 2、引物荧光标记,采用PCR-毛细管电泳法,检测ASPN天冬氨酸(D)重复多态性在AS和正常对照人群的分布情况,分析其与AS临床表型的关联。 3、检索分析已发表的有关AS和SpA的全基因扫描文献结果,采用GSMA软件进行Meta分析。 4、检索分析已发表的有关AS与肿瘤坏死因子α基因启动子—308位点多态性的文献结果,采用Review Manager4.2软件进行Meta分析。 结果:1、经HWE检测,PD-1 rs2227981C/T各基因型在AS组和正常对照组的分布符合遗传平衡(P=0.711;P=0.17668)。统计分析显示,PD-1 rs2227981各等位基因及基因型在AS患者组和正常对照组的分布无明显差异(P=0.226;P=0.283)。 2、经HWE检测,PD-1 rs2227982C/T各基因型在AS组和正常对照组的分布符合遗传平衡(P=0.1712;P=0.0556)。统计分析显示,AS患者组PD-1 rs2227982T/T、C/T和C/C基因型频率分别为9.69%、36.22%和54.08%,正常对照组为5%、24.44%和70.56%,二者分布有统计学差异(P=0.004);PD-1rs2227982T在AS组频率明显增高(28.53%Vs17.22%;P=0.000)。按性别因素进行亚群分析,在男性亚群中,PD-1 rs2227982各等位基因及基因型在AS组频率亦明显增高(P=0.004;P=0.019);在女性亚群中,PD-1 rs2227982T在AS组频率增高(P=0.004),各基因型则未见统计学差异(P=0.089)。 3、PD-1 rs2227981、rs2227982单倍体分析表明,CT单倍体在AS组频率明显高于对照组(19.2%Vs11.4%;P=0.003),CC单倍体在对照组常见(47.1%Vs59.9%;P=0.001)。 4、PD-1 rs2227982各基因型与AS临床表型的关联分析表明,TT基因型组AS患者双髋关节和单侧膝关节受累频率明显增加(P=0.000;P=0.003),骶髂关节破坏程度较重(P=0.000)。 5、经HWE检测,PD-L1 rs822336C/G各基因型在AS组和正常对照组的分布符合遗传平衡(P=0.1477;P=0.0794)。统计分析显示,AS患者组PD-L1 rs822336C/C、C/G和G/G基因型频率分别为9.69%、48.98%和40.31%,正常对照组为10%、34.44%和55.56%,二者分布有统计学差异(P=0.007)。PD-L1 rs822336C在AS组频率明显增高(34.69%Vs27.22%;P=0.027)。按性别因素进行亚群分析,男性亚群中PD-L1 rs822336各等位基因及基因型在AS组频率亦明显增高(P=0.005;P=0.002),在女性亚群各等位基因及基因型均未见统计学差异(P=0.454;P=0.731)。 6、PD-L1 rs822336各基因型与AS临床表型的关联分析表明,CC基因型组AS患者腰痛和虹膜炎阳性率明显升高(P=0.037;P=0.000);骶髂关节炎则以CC和CG基因型两组较重(P=0.002)。 7、经HWE检测,PD-L2 rs1009759各基因型在AS组和正常对照组的分布符合遗传平衡(P=0.1740;P=0.1902)。统计分析显示,PD-L2 rs1009759各等位基因及基因型在AS患者组和正常对照组的分布无明显差异(P=0.371;P=0.695) 8、经HWE检测,PD-L2 rs6476985各基因型在AS组和正常对照组的分布符合遗传平衡(P=0.6747:P=0.0517)。统计分析显示,PD-L2