Mechanisms of initiation of skeletal mineralization

骨骼矿化的起始机制

• 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
• 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

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（由申请方提供）：软骨内骨化是一个由矿化促进剂和抑制剂介导的精心策划的过程。实验证据表明，细胞外基质中以及软骨细胞和成骨细胞衍生的基质囊泡（MV）的腔内，沿着胶原纤维存在羟基磷灰石晶体。磷酸酶也参与其中，但它们的身份和功能仍不清楚。我们的工作集中在阐明三种磷酸酶，PHOSPHO 1，组织非特异性碱性磷酸酶（TNAP）和核苷三磷酸焦磷酸水解酶（NPP 1）在建立一个有利于控制生理骨骼矿化的Pi/PPi比例的协同作用。我们目前的骨骼矿化启动机制的模型涉及囊内PHOSPHO 1功能和Pi流入MVs中的矿化启动以及TNAP，NPP 1在囊外矿化进程中的功能。这种假设驱动的竞争性更新应用旨在测试骨骼矿化起始的这种综合模型的关键方面，该模型统一了许多不同的生化观察，例如，通过PHOSPHO 1的囊内Pi生成，TNAP的Pi生成与PPi降解，MV中Pi转运蛋白的作用，对局部产生的Pi与全身Pi的需要，以及MV介导的与胶原介导的ECM矿化。该提案还将推进重要的翻译研究，以了解Phospho 1基因突变可能参与早发性脊柱侧凸和成骨性脊柱侧凸样综合征的发展，Phospho 1基因突变对低磷酸酶症严重程度的可能复合效应，以及PHOSPHO 1在中膜血管钙化中的假定作用，这是一种在终末期肾病、肥胖、糖尿病和衰老中发病率较高的疾病。 公共卫生相关性：我们的工作重点是阐明三种磷酸酶（PHOSPHO 1，TNAP和NPP 1）在骨骼矿化启动过程中的功能相互作用，这是一个对所有脊椎动物物种（包括小鼠和人类）至关重要的过程。这些磷酸酶功能的改变导致软骨病，包括佝偻病、骨软化、自发性骨折、牙齿脱落以及骨关节炎和动脉钙化形式的软组织不适当钙化。我们的工作对罕见疾病有明确的转化应用，如低磷酸酶症和成骨不全症，也对常见疾病有明确的转化应用，包括脊柱侧凸、骨关节炎和内侧血管钙化。