The role of phosphatases in the initiation of skeletal mineralization.
TLDR
It is shown that PHOSPHO1, a soluble phosphatase with specificity for two molecules present in MVs, phosphoethanolamine and phosphocholine, is responsible for initiating HA crystal formation inside MVs and that PHosPHO 1 and TNAP have nonredundant functional roles during endochondral ossification.Abstract:
Endochondral ossification is a carefully orchestrated process mediated by promoters and inhibitors of mineralization. Phosphatases are implicated, but their identities and functions remain unclear. Mutations in the tissue-nonspecific alkaline phosphatase (TNAP) gene cause hypophosphatasia, a heritable form of rickets and osteomalacia, caused by an arrest in the propagation of hydroxyapatite (HA) crystals onto the collagenous extracellular matrix due to accumulation of extracellular inorganic pyrophosphate (PPi), a physiological TNAP substrate and a potent calcification inhibitor. However, TNAP knockout (Alpl(-/-)) mice are born with a mineralized skeleton and have HA crystals in their chondrocyte- and osteoblast-derived matrix vesicles (MVs). We have shown that PHOSPHO1, a soluble phosphatase with specificity for two molecules present in MVs, phosphoethanolamine and phosphocholine, is responsible for initiating HA crystal formation inside MVs and that PHOSPHO1 and TNAP have nonredundant functional roles during endochondral ossification. Double ablation of PHOSPHO1 and TNAP function leads to the complete absence of skeletal mineralization and perinatal lethality, despite normal systemic phosphate and calcium levels. This strongly suggests that the Pi needed for initiation of MV-mediated mineralization is produced locally in the perivesicular space. As both TNAP and nucleoside pyrophosphohydrolase-1 (NPP1) behave as potent ATPases and pyrophosphatases in the MV compartment, our current model of the mechanisms of skeletal mineralization implicate intravesicular PHOSPHO1 function and Pi influx into MVs in the initiation of mineralization and the functions of TNAP and NPP1 in the extravesicular progression of mineralization.read more
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Journal ArticleDOI
Effects of pH on the production of phosphate and pyrophosphate by matrix vesicles' biomimetics.
TL;DR: This work has shown that a slight pH elevation facilitates mineralization, especially via upregulated PPi hydrolysis by both NPP1 and TNAP, further elevating the Pi/PPi ratio, thus enhancing bone mineralization.
Journal ArticleDOI
Matrix Vesicles: Role in Bone Mineralization and Potential Use as Therapeutics
Sana Ansari,Bregje W. M. de Wildt,Michelle A. M. Vis,Carolina E de Korte,Keita Ito,Sandra Hofmann,Yuana Yuana +6 more
TL;DR: In this paper, the role of matrix vesicles (MtVs) in bone formation and mineralization is discussed, as well as their potential application for bone pathologies and bone regeneration.
Journal ArticleDOI
The Functional co-operativity of Tissue-Nonspecific Alkaline Phosphatase (TNAP) and PHOSPHO1 during initiation of Skeletal Mineralization.
Carmen Huesa,Dean Houston,Tina Kiffer-Moreira,Manisha C. Yadav,José Luis Millán,Colin Farquharson +5 more
TL;DR: Critical non-redundant roles for PHOSPHO1 and TNAP during the initiation of osteoblast and chondrocyte mineralization are suggested.
Journal ArticleDOI
Overlapping functions of bone sialoprotein and pyrophosphate regulators in directing cementogenesis
M. Ao,Michael B. Chavez,Emily Y. Chu,K.C. Hemstreet,Y. Yin,Manisha C. Yadav,José Luis Millán,L.W. Fisher,Harvey A. Goldberg,Martha J. Somerman,Brian L. Foster +10 more
TL;DR: P perturbations in PPi metabolism are not solely driving the cementum pathology in Bsp-/- mice, and that PPi is more potent than BSP as a cementum regulator, as shown by the ability to override loss of BSP by lowering PPi.
Journal ArticleDOI
Skeletal mineralization: mechanisms and diseases
TL;DR: In addition to various forms of rickets/osteomalacia, hypophosphatasia (HPP) is characterized by impaired skeletal mineralization, and unraveling its pathogenesis will lead to more precise diagnoses and effective treatments.
References
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Book
The Metabolic and Molecular Bases of Inherited Disease
TL;DR: In this paper, the authors present a list of disorders of MITOCHONDRIAL FUNCTION, including the following: DISORDERS OF MIOCHONDRIC FERTILITY XIX, XVI, XIX.
Journal ArticleDOI
Vesicles associated with calcification in the matrix of epiphyseal cartilage
TL;DR: It is suggested that matrix vesicles are derived from cells and that they may play a role in initiating calcification at the epiphysis.
Journal ArticleDOI
Tissue-nonspecific alkaline phosphatase and plasma cell membrane glycoprotein-1 are central antagonistic regulators of bone mineralization
Lovisa Hessle,Kristen Johnson,H. Clarke Anderson,Sonoko Narisawa,Adnan Sali,James W. Goding,Robert Terkeltaub,José Luis Millán +7 more
TL;DR: The results suggest that inhibiting PC-1 function may be a viable therapeutic strategy for hypophosphatasia, and interfere with TNAP activity may correct pathological hyperossification because of PPi insufficiency.
Journal ArticleDOI
The Possible Significance of Hexosephosphoric Esters in Ossification.
TL;DR: Robison was able to study for two years in Leipzig in the kdbordtories of Professor Hantz as mentioned in this paper, where he obtained a scholarship to attend the University of Nottingham.
Journal ArticleDOI
Role of the mouse ank gene in control of tissue calcification and arthritis.
TL;DR: It is shown that the mouse progressive ankylosis locus encodes a multipass transmembrane protein (ANK) that is expressed in joints and other tissues and controls pyrophosphate levels in cultured cells.
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