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Enhanced but hypofunctional osteoclastogenesis in an autosomal dominant osteopetrosis type II case carrying a c.1856C>T mutation in CLCN7.
Bone Research ( IF 12.7 ) Pub Date : 2016-12-19 , DOI: 10.1038/boneres.2016.35
Xiang Chen 1 , Kun Zhang 1 , Janet Hock 2 , Chunyu Wang 1 , Xijie Yu 1
Affiliation  

Type II autosomal dominant osteopetrosis (ADO2), which is the most common form of osteopetrosis, is caused by heterozygous mutations in the chloride channel 7 (CLCN7) gene. The osteopetrosis of ADO2 has been attributed to hypofunctional osteoclasts. The mechanism underlying the abnormality in osteoclast function remains largely unknown. This study was designed to investigate gene mutations and osteoclast function in a case that was clinically diagnosed as ADO2. Genomic DNA was extracted from blood samples of this patient, and the 25 exons of CLCN7 were amplified. Peripheral blood from the ADO2 subject and a healthy age- and sex-matched control was used to evaluate osteoclastogenesis, osteoclast morphology, and bone resorption. Analysis of DNA from the patient showed a germline heterozygous missense mutation, c.1856C>T (p.P619L), in exon 20 of CLCN7. A similar homozygous mutation at this site was previously reported in a patient with autosomal recessive osteopetrosis. When cultured, the peripheral blood mononuclear cells (PBMCs) from the ADO2 patient spontaneously differentiated into mature osteoclasts in vitro. The ADO2 patient's PBMCs formed enhanced, but heterogeneous, osteoclasts in both the presence and absence of macrophage-colony stimulating factor, and nuclear factor-ĸB ligand. Bone resorption was reduced in the ADO2 patient's osteoclasts, which exhibited aberrant morphology and abnormal distribution of integrin avβ3. Gene analysis found increased c-fos expression and reduced RhoA and integrin beta 3 expression in ADO2 cells. In conclusion, our data suggest that enhanced, heterogeneous osteoclast induction may be an intrinsic characteristic of ADO2.

中文翻译:

在常染色体显性II型骨质疏松症病例中,在CLCN7中带有c.1856C> T突变的情况下,破骨细胞生成增强但功能低下。

II型常染色体显性骨质骨化病(ADO2)是最常见的骨质化形式,是由氯化物通道7(CLCN7)基因的杂合突变引起的。ADO2的骨质疏松症已归因于功能低下的破骨细胞。破骨细胞功能异常的潜在机制在很大程度上尚不清楚。这项研究旨在调查在临床诊断为ADO2的情况下的基因突变和破骨细胞功能。从该患者的血液样本中提取基因组DNA,并扩增了25个CLCN7外显子。使用来自ADO2受试者的外周血以及健康的年龄和性别匹配的对照来评估破骨细胞生成,破骨细胞形态和骨吸收。对患者DNA的分析显示出种系杂合错义突变,c.1856C> T(p.P619L),在CLCN7的第20外显子中。以前曾报道常染色体隐性骨质疏松症患者在此位点有类似的纯合突变。培养后,来自ADO2患者的外周血单核细胞(PBMC)在体外自发分化为成熟的破骨细胞。在存在和不存在巨噬细胞集落刺激因子和核因子-colB配体的情况下,ADO2患者的PBMC均形成增强的但异质的破骨细胞。ADO2患者的破骨细胞的骨吸收减少,表现出异常的形态和整联蛋白avβ3的异常分布。基因分析发现ADO2细胞中c-fos表达增加,RhoA和整联蛋白beta 3表达降低。总之,我们的数据表明,增强的异源破骨细胞诱导可能是ADO2的固有特征。以前曾报道常染色体隐性骨质疏松症患者在此位点有类似的纯合突变。培养后,来自ADO2患者的外周血单核细胞(PBMC)在体外自发分化为成熟的破骨细胞。在存在和不存在巨噬细胞集落刺激因子和核因子-colB配体的情况下,ADO2患者的PBMC均形成增强的但异质的破骨细胞。ADO2患者的破骨细胞的骨吸收减少,表现出异常的形态和整联蛋白avβ3的异常分布。基因分析发现ADO2细胞中c-fos表达增加,RhoA和整联蛋白beta 3表达降低。总之,我们的数据表明,增强的异源破骨细胞诱导可能是ADO2的固有特征。以前曾报道常染色体隐性骨质疏松症患者在此位点有类似的纯合突变。培养后,来自ADO2患者的外周血单核细胞(PBMC)在体外自发分化为成熟的破骨细胞。在存在和不存在巨噬细胞集落刺激因子和核因子-colB配体的情况下,ADO2患者的PBMC均形成增强的但异质的破骨细胞。ADO2患者的破骨细胞的骨吸收减少,表现出异常的形态和整联蛋白avβ3的异常分布。基因分析发现ADO2细胞中c-fos表达增加,RhoA和整联蛋白beta 3表达降低。总之,我们的数据表明,增强的异源破骨细胞诱导可能是ADO2的固有特征。
更新日期:2019-11-01
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