Mechanisms of initiation of skeletal mineralization

骨骼矿化的起始机制

基本信息

批准号：
8245524
负责人：
JOSE LUIS MILLAN
金额：
$ 42.98万
依托单位：
SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-09-15 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8245524
关键词：
2-Oxoglutarate 5-Dioxygenase Procollagen-Lysine ATP phosphohydrolase Ablation Aging Alkaline Phosphatase Biochemical Biochemical Pathway Blood Vessels Calcified Carbonates Chondrocytes Collagen Collagen Fibril Crystal Formation Degenerative polyarthritis Development Diabetes Mellitus Diphosphates Disease End stage renal failure Epiphysial cartilage Extracellular Matrix Fracture Gene Mutation Generations Genes Hardness Human Hydroxyapatites Hypophosphatasia Knock-out Lead Life Medial Mediating Microscopy Minerals Modeling Morbidity - disease rate Mus Mutation Nucleosides Obesity Osteoblasts Osteogenesis Imperfecta Osteomalacia Pathological fracture Peptidylprolyl Isomerase Perinatal Phenotype Phosphoric Monoester Hydrolases Phosphorylcholine Physiological Plasma Process Progress Reports Rare Diseases Rickets Role Severities Skeleton Smooth Muscle Myocytes Specificity Syndrome Testing Tissues Tooth Loss Transgenic Organisms Vascular calcification Vertebrates Vesicle Work bone calcification calcium phosphate crosslink early onset extracellular inhibitor/antagonist innovation long bone mineralization nanoindentation phosphoethanolamine promoter scoliosis skeletal soft tissue tibia translational study

项目摘要

DESCRIPTION (provided by applicant): Endochondral ossification is a carefully orchestrated process mediated by promoters and inhibitors of mineralization. Experimental evidence has pointed to the presence of hydroxyapatite crystals along collagen fibrils in the extracellular matrix and also within the lumen of chondrocyte- and osteoblast-derived matrix vesicles (MVs). Phosphatases are implicated, but their identities and functions remain unclear. Our work centers on elucidating the concerted action of three phosphatases, PHOSPHO1, tissue-nonspecific alkaline phosphatase (TNAP) and nucleosidetriphosphate pyrophosphohydrolase (NPP1) in establishing a Pi/PPi ratio conducive to controlled physiological skeletal mineralization. Our current model of the mechanisms of initiation of skeletal mineralization implicate intra-vesicular PHOSPHO1 function and Pi influx into MVs in the initiation of mineralization and the functions of TNAP, NPP1 in the extra-vesicular progression of mineralization. This hypothesis-driven competitive renewal application seeks to test crucial aspects of this comprehensive model of initiation of skeletal mineralization that unifies a number of disparate biochemical observations, e.g., intravesicular Pi-generation by PHOSPHO1, Pi-generation versus PPi-degradation by TNAP, the role of Pi- transporters in MVs, the need for locally produced Pi versus systemic Pi, and MV-mediated versus collagen- mediated ECM mineralization. This proposal will also advance significant translational studies into the possible involvement of Phospho1 gene mutations in the development of early-onset scoliosis and osteogenesis imperfecta-like syndrome, the possible compounding effect of Phospho1 gene mutations on the severity of hypophosphatasia, and the putative role of PHOSPHO1 in medial vascular calcification, a condition with high morbidity in end-stage renal disease, obesity, diabetes and aging. PUBLIC HEALTH RELEVANCE: Our work focuses on elucidating the functional interplay of three phosphatases (PHOSPHO1, TNAP and NPP1) during the initiation of skeletal mineralization, a process of fundamental importance to all vertebrate animal species, including mice and humans. Alterations in the function of these phosphatases lead to soft bone conditions, including rickets, osteomalacia, spontaneous fractures, loss of teeth as well as inappropriate calcification of soft tissues in the form of osteoarthritis and arterial calcification. Our work has clear translational applications to rare diseases, such as hypophosphatasia and osteogenesis imperfecta, and also prevalent diseases, including scoliosis, osteoarthritis and medial vascular calcification.

描述（由申请人提供）：内侧软骨骨化是由启动子和矿化抑制剂介导的精心策划的过程。实验证据表明，沿细胞外基质中的胶原原纤维以及软骨细胞和成骨细胞衍生的基质囊泡（MVS）的腔内存在羟基磷灰石晶体。磷酸酶是涉及的，但它们的身份和功能尚不清楚。我们的工作集中在阐明三种磷酸酶，磷酸化酶，组织非特异性碱性磷酸酶（TNAP）和核分型甲磷酸二磷酸酚磷酸酶（NPP1）方面的协同作用，以建立PI/PPI比率有益于对受控生理生理学骨架骨架骨骼矿物质的受控比率。我们目前的骨骼矿化机制模型暗示了在矿化的启动和TNAP的功能中，在矿化外矿化和矿化外进展中，在矿化的启动和tnap的功能中，施加磷酸化磷酸1的功能和PI涌入。这一假设驱动的竞争性更新应用程序旨在测试这种骨骼矿化启动的全面模型的关键方面，该模型统一了许多不同的生化观察，例如，磷酸化，ppi-ppi-ppi-ppigentor tnap，Pi-pi-pi-pi-pi-pi-pi-pi-pi-pi-pi-pi-pi-po-pere tnap的角色，ppi-ppi-tnap的角色，M.与全身性PI，以及MV介导的与胶原蛋白介导的ECM矿化。这项提议还将推动大量的转化研究，以使磷酸1基因突变可能参与早期发作的脊柱侧弯和成骨的形成不完美的综合征的发展，磷酸1基因突变对磷酸磷酸磷酸磷酸的严重性以及磷酸化高度元素的疾病的疾病的疾病的疾病，磷酸磷酸磷酸的作用的复合作用可能会产生。糖尿病和衰老。公共卫生相关性：我们的工作着重于阐明在骨骼矿化开始期间三种磷酸酶（磷酸1，TNAP和NPP1）的功能相互作用，这是对包括小鼠和人类在内的所有脊椎动物物种的基本重要性的过程。这些磷酸酶功能的改变会导致柔软的骨骼条件，包括rick骨，骨乳核酸，自发性裂缝，牙齿的丧失以及骨关节炎和动脉钙化形式的软组织的不适当钙化。我们的工作对罕见疾病（例如下磷酸和成骨症质不完美）以及普遍的疾病（包括脊柱侧弯，骨关节炎和内侧血管钙化）具有明显的翻译应用。