Control of Bone Formation in Craniometaphyseal Dysplasia

颅骨干骺端发育不良中骨形成的控制

• 批准号: 8249380
• 负责人: ERNST J REICHENBERGER
• 金额: $ 36.58万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8249380
• 关键词: Actins; Affect; Albers-Schonberg disease; Animal Model; Ankylosis; Auditory; Bone Diseases; Bone Marrow Transplantation; Bone Matrix; Bone Resorption; Bone remodeling; Caliber; Calvaria; Cells; Cephalic; Characteristics; Conductive hearing loss; Cytoskeleton; Diet; Diphosphates; Disease; Dissection; Dysplasia; Environment; Equilibrium; Extracellular Matrix; Facial paralysis; Flare; Functional disorder; Future; Gene Expression Regulation; Genes; Genetic; Goals; Homeostasis; Human; Hydroxyapatites; Hyperostosis; Impairment; In Vitro; Integral Membrane Protein; Intracellular Transport; Knock-in Mouse; Knockout Mice; Lead; Metaphysis; Minerals; Modeling; Molecular; Mus; Mutation; Neurons; Nodule; Operative Surgical Procedures; Orphan Disease; Osteoblasts; Osteoclasts; Osteocytes; Osteogenesis; Osteoporosis; Pathogenesis; Patients; Phenotype; Phenylalanine; Physiologic calcification; Population; Publishing; Regulation; Role; Serum; Staging; Testing; Therapeutic Intervention; Transgenic Mice; Visual; bone; bone cell; bone mass; cell type; craniofacial; extracellular; face bone structure; gain of function; homologous recombination; in vivo; in vivo Model; inhibitor/antagonist; inorganic phosphate; long bone; loss of function; middle ear; mineralization; mouse model; mutant; novel therapeutic intervention; osteoblast differentiation; promoter; public health relevance; research study; skeletal

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. PUBLIC HEALTH RELEVANCE: The questions we ask in this application seek to understand the consequences of the CMD mutation on bone remodeling and to investigate mechanisms that lead to the CMD-like phenotype in our Ank knock-in mouse model. We expect that understanding mechanisms that lead to CMD will help to develop strategies for therapeutic intervention for this debilitating disorder. We also expect a broad impact on the field of bone remodeling as the mutation in this animal model affects some key mechanisms for bone mineralization and regulation of bone cells.

描述（由申请人提供）：颅骺端发育不良（CMD）是一种罕见的遗传性骨病，可导致颅面骨肥大和长骨干骺端外展。我们通过同源重组将最常见的CMD突变之一Phe 377缺失引入小鼠Ank基因，从而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）转运至细胞外环境。PPi是骨中矿化的重要调节剂。Ank Phe 377 del基因敲入小鼠出现颅骨和面骨肥大、颅孔直径减小和骨小梁下干骺端变宽，从而表达CMD的骨骼特征。在本申请中，我们提出1）研究磷酸盐和焦磷酸盐在AnkKI/KI小鼠模型的低矿化表型中的作用，以及2）研究ANK Phe 377 del突变对成骨细胞生成期间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分子控制机制，调节骨形成和骨重建的患者CMD或类似的颅管条件。该Ank Phe 377 del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稳态的理解产生广泛影响，并预计将影响未来对CMD和相关疾病的治疗。更好地了解骨矿化和控制骨量的机制对于大部分患有骨形成和骨吸收失衡的人群（包括骨质疏松症和骨硬化症患者）非常重要。 公共卫生关系：我们在本申请中提出的问题旨在了解CMD突变对骨重建的影响，并研究导致Ank基因敲入小鼠模型中CMD样表型的机制。我们希望了解导致CMD的机制将有助于制定这种衰弱性疾病的治疗干预策略。我们还期望在骨重建领域产生广泛的影响，因为该动物模型中的突变影响了骨矿化和骨细胞调节的一些关键机制。