CLCN7 and TCIRG1 Mutations Differentially Affect Bone Matrix Mineralization in Osteopetrotic Individuals
CLCN7 and TCIRG1 Mutations Differentially Affect Bone Matrix Mineralization in Osteopetrotic Individuals
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DOI：
10.1002/jbmr.2100
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发表时间：
2014-04-01
影响因子：
6.2
通讯作者：
Amling, Michael
中科院分区：
文献类型：
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作者：
Barvencik, Florian;Kurth, Ingo;Amling, Michael
骨质疏松症是一种骨吸收受损的遗传性疾病，最常受影响的基因是clcn7和tcirg1，分别编码Cl - /H+交换器CLC‐7和空泡H+‐atp酶的a3亚基。我们和其他人之前已经表明，该疾病经常伴有骨软化症，并且在Tcirg1‐deficient / oc小鼠中也发现了这种额外的病理。剩下的问题是类骨富集是否与TCIRG1失活特异性相关，或者clcn7突变是否也会导致骨骼矿化缺陷。在这里，我们对一个携带新突变inCLCN7（D145G）的家族进行了完整的骨学评估，该突变损害了CLC‐7离子转运体的激活和松弛动力学。在纯合子状态下携带突变的两个兄弟姐妹表现出高骨量，骨形成标志物的血清水平增加，但与其他家庭成员相比，钙稳态没有受损。然而，最重要的是，一名受影响儿童的髂嵴活检的未钙化处理清楚地显示了骨小梁骨量的病理性增加，但没有骨软化的迹象。考虑到这些发现的潜在相关性，我们还对另外7例由突变inTNFRSF11A（n= 1）、CLCN7（n= 3）或tcirg1 （n= 3）引起的骨质疏松症患者进行了未钙化组织学的髂骨活检。在这里，我们观察到所有依赖tcirg1的骨质疏松病例都表现出严重的类骨积累和矿化基质内钙含量降低。相比之下，tnfrsf11a依赖性或clcn7依赖性骨质疏松症患者没有可检测到的骨矿化缺陷。综上所述，我们的分析表明clcn7和tcirg1突变对骨基质矿化的影响是不同的，因此有必要修改目前的骨质疏松分类。©2014美国骨与矿物研究学会。
Osteopetrosis is an inherited disorder of impaired bone resorption, with the most commonly affected genes beingCLCN7andTCIRG1, encoding the Cl−/H+exchanger CLC‐7 and the a3 subunit of the vacuolar H+‐ATPase, respectively. We and others have previously shown that the disease is frequently accompanied by osteomalacia, and that this additional pathology is also found in Tcirg1‐deficientoc/ocmice. The remaining question was whether osteoid enrichment is specifically associated with TCIRG1 inactivation, or whetherCLCN7mutations would also cause skeletal mineralization defects. Here we describe a complete osteologic assessment of one family carrying a novel mutation inCLCN7(D145G), which impairs the activation and relaxation kinetics of the CLC‐7 ion transporter. The two siblings carrying the mutation in the homozygous state displayed high bone mass, increased serum levels of bone formation markers, but no impairment of calcium homeostasis when compared to the other family members. Most importantly, however, undecalcified processing of an iliac crest biopsy from one of the affected children clearly demonstrated a pathological increase of trabecular bone mass, but no signs of osteomalacia. Given the potential relevance of these findings we additionally performed undecalcified histology of iliac crest biopsies from seven additional cases with osteopetrosis caused by a mutation inTNFRSF11A(n= 1),CLCN7(n= 3), orTCIRG1(n= 3). Here we observed that all cases withTCIRG1‐dependent osteopetrosis displayed severe osteoid accumulation and decreased calcium content within the mineralized matrix. In contrast, there was no detectable bone mineralization defect in the cases withTNFRSF11A‐dependent orCLCN7‐dependent osteopetrosis. Taken together, our analysis demonstrates thatCLCN7andTCIRG1mutations differentially affect bone matrix mineralization, and that there is a need to modify the current classification of osteopetrosis. © 2014 American Society for Bone and Mineral Research.