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Mechanisms of initiation of skeletal mineralization

骨骼矿化的起始机制

基本信息

批准号：
8915048
负责人：
JOSE LUIS MILLAN
金额：
$ 43.88万
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 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8915048
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.

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，羟基磷灰石晶体沿着胶原纤维存在于细胞外基质中，也存在于软骨细胞和成骨细胞衍生的基质囊泡（MV）的内腔中。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。

项目成果

期刊论文数量（14）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Reference point indentation is not indicative of whole mouse bone measures of stress intensity fracture toughness.

参考点的压痕并不表示全鼠骨骼的应力强度骨折韧性的测量。

DOI：
10.1016/j.bone.2014.09.020
发表时间：
2014-12
期刊：
BONE
影响因子：
4.1
作者：
Carriero, Alessandra;Bruse, Jan L.;Oldknow, Karla J.;Millan, Jose Luis;Farquharson, Colin;Shefelbine, Sandra J.
通讯作者：
Shefelbine, Sandra J.

PHOSPHO1 is a skeletal regulator of insulin resistance and obesity.

DOI：
10.1186/s12915-020-00880-7
发表时间：
2020-10-22
期刊：
BMC biology
影响因子：
5.4
作者：
Suchacki KJ;Morton NM;Vary C;Huesa C;Yadav MC;Thomas BJ;Turban S;Bunger L;Ball D;Barrios-Llerena ME;Guntur AR;Khavandgar Z;Cawthorn WP;Ferron M;Karsenty G;Murshed M;Rosen CJ;MacRae VE;Millán JL;Farquharson C
通讯作者：
Farquharson C

Phospho1 deficiency transiently modifies bone architecture yet produces consistent modification in osteocyte differentiation and vascular porosity with ageing.

DOI：
10.1016/j.bone.2015.07.035
发表时间：
2015-12
期刊：
Bone
影响因子：
4.1
作者：
Javaheri B;Carriero A;Staines KA;Chang YM;Houston DA;Oldknow KJ;Millan JL;Kazeruni BN;Salmon P;Shefelbine S;Farquharson C;Pitsillides AA
通讯作者：
Pitsillides AA

Mineralisation of collagen rich soft tissues and osteocyte lacunae in Enpp1(-/-) mice.

DOI：
10.1016/j.bone.2014.09.016
发表时间：
2014-12
期刊：
BONE
影响因子：
4.1
作者：
Hajjawi, Mark O. R.;MacRae, Vicky E.;Huesa, Carmen;Boyde, Alan;Millan, Jose Luis;Arnett, Timothy R.;Orriss, Isabel R.
通讯作者：
Orriss, Isabel R.

The appearance and modulation of osteocyte marker expression during calcification of vascular smooth muscle cells.