Control of Bone Formation in Craniometaphyseal Dysplasia

描述（由申请人提供）：颅干骺端发育不良（CMD）是一种罕见的遗传性骨骼疾病，导致颅面骨增生和长骨的隆起。我们通过同源重组将最常见的CMD突变之一Phe377缺失引入小鼠Ank基因，建立了这种孤儿病的动物模型。ANK是一种跨膜蛋白，已知可将细胞内焦磷酸盐（PPi）转运到细胞外环境。PPi是骨矿化的重要调节因子。Ank Phe377del敲入小鼠颅骨和面骨增厚，颅孔直径减小，骨外骨小梁下加宽，从而表达CMD的骨骼特征。在本应用中，我们提出：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突变对成骨细胞发生过程中特定分化阶段基因调控的直接影响。3)我们将研究破骨细胞对AnkKI/KI小鼠骨量表型的贡献。我们的长期目标是研究CMD或类似颅管疾病患者骨形成和骨重塑的分子控制机制。这个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。这些研究将对我们对骨稳态的理解产生广泛的影响，并有望影响CMD和相关疾病的未来治疗。更好地了解骨矿化和骨量控制的机制对骨形成和吸收失衡的大部分人群（包括骨质疏松症和骨质疏松症患者）是重要的。

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.