Control of Bone Formation in Craniometaphyseal Dysplasia

描述(申请人提供)：颅骨干骺端发育不良(CMD)是一种罕见的遗传性骨骼疾病，导致头面部骨骼肥大和长骨干骺端膨大。我们通过同源重组将最常见的CMD突变之一Phe377缺失引入到小鼠的Ank基因中，从而创建了这种孤儿疾病的动物模型。ANK是一种跨膜蛋白，可以将细胞内的焦磷酸(PPI)转运到细胞外环境中。PPI是骨矿化的重要调节因子。ANK Phe377del基因敲除小鼠出现颅骨和面骨骨质增厚，颅孔直径缩小，干骺端欠骨小梁增宽，从而表现出CMD的骨骼特征。在这一应用中，我们建议1)研究磷酸盐和焦磷酸盐在AnkKI/KI小鼠模型低矿化表型中的作用；2)研究ANK Phe377del突变对成骨细胞形成过程中特定分化阶段的基因调控的直接影响。3)研究破骨细胞在AnkKI/Ki小鼠骨量表型中的作用。我们的长期目标是研究调控CMD或类似颅管疾病患者骨形成和骨重建的分子控制机制。Ank Phe377del敲入模型是第一个完全复制CMD表型的模型，使我们能够在体内模型中研究CMD的病理生理学。这些研究将对我们对骨骼稳态的理解产生广泛的影响，并有望影响未来对CMD和相关疾病的治疗。对于骨形成和骨吸收失衡的人群，包括骨质疏松症和骨化症患者，更好地了解骨矿化和骨量控制的机制是非常重要的。

DESCRIPTION (provided by applicant): Craniometaphyseal dysplasia (CMD) is a rare genetic bone disorder, which results in hyperostosis of craniofacial bones and flaring of metaphyses in long bones. We have created an animal model for this orphan disease by introducing one of the most common CMD mutations, a Phe377 deletion, into the mouse Ank gene by homologous recombination. ANK is a transmembrane protein known to transport intracellular pyrophosphate (PPi) into the extracellular environment. PPi is an important regulator of mineralization in bone. Ank Phe377del knock-in mice develop hyperostotic cranial and facial bone, reduced diameters of cranial foramina and undertrabeculated widened metaphyses, thus expressing the skeletal hallmarks of CMD. In this application, we propose 1) to study the role of phosphate and pyrophosphate in the hypomineralization phenotype of the AnkKI/KI mouse model and 2) to investigate direct effects of the ANK Phe377del mutation on gene regulation of specific differentiation stages during osteoblastogenesis. 3) We will investigate the contribution of osteoclasts to the bone mass phenotype of AnkKI/KI mice. Our long-term goal is to study molecular control mechanisms that regulate bone formation and bone remodeling in patients with CMD or similar craniotubular conditions. This Ank Phe377del knock-in model is the first to fully replicate the CMD phenotype enabling us to study the pathophysiology of CMD in an in vivo model. These studies will have broad impact on our understanding of bone homeostasis and are expected to impact future treatment of CMD and related disorders. A better understanding of mechanisms for bone mineralization and control of bone mass is important for large segments of the population who suffer from imbalance of bone formation and resorption, including patients with osteoporosis and osteopetrosis.