Mechanisms of initiation of skeletal mineralization

骨骼矿化的起始机制

• 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
• 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

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（由申请人提供）：软骨内骨化是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，沿着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 (MV) 的管腔内存在羟基磷灰石晶体。磷酸酶参与其中，但其身份和功能仍不清楚。我们的工作重点是阐明三种磷酸酶 PHOSPHO1、组织非特异性碱性磷酸酶 (TNAP) 和核苷三磷酸焦磷酸水解酶 (NPP1) 在建立有利于受控生理骨骼矿化的 Pi/PPi 比率方面的协同作用。我们目前的骨骼矿化启动机制模型涉及囊泡内 PHOSPHO1 功能和 Pi 在矿化启动中流入 MV，以及 TNAP、NPP1 在囊泡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启动综合模型的关键方面，该模型统一了许多不同的生化观察结果，例如 PHOSPHO1 的囊泡内 Pi 生成、TNAP 的 Pi 生成与 PPi 降解、Pi 转运蛋白在 MV 中的作用、本地产生 Pi 的需求 与全身 Pi 的比较，以及 MV 介导的与胶原介导的 ECM 矿化的比较。该提案还将推进重要的转化研究，包括 Phospho1 基因突变可能参与早发性脊柱侧凸和成骨不全样综合征的发生、Phospho1 基因突变对低磷酸酯酶症严重程度可能产生的复合效应，以及 PHOSPHO1 在内侧血管钙化（终末期肾病、肥胖症的高发病率）中的假定作用。 糖尿病和衰老。

项目成果

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.

• DOI: 10.1371/journal.pone.0019595
• 发表时间: 2011
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Zhu D;Mackenzie NC;Millán JL;Farquharson C;MacRae VE
• 通讯作者: MacRae VE