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
Citations
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Journal ArticleDOI
Improvement of the skeletal and dental hypophosphatasia phenotype in Alpl-/- mice by administration of soluble (non-targeted) chimeric alkaline phosphatase.
Kellen Cristina da Silva Gasque,Brian L. Foster,Pia Kuss,Manisha C. Yadav,Jin Liu,Tina Kiffer-Moreira,Andrea van Elsas,Nan E. Hatch,Martha J. Somerman,José Luis Millán +9 more
TL;DR: This study provides the first evidence for the pharmacological efficacy of ChimAP for use in the treatment of skeletal and dental manifestations of HPP in Alpl(-/-) mice.
Journal ArticleDOI
Ablation of osteopontin improves the skeletal phenotype of phospho1(-/-) mice.
Manisha C. Yadav,Carmen Huesa,Sonoko Narisawa,Marc Hoylaerts,Alain Moreau,Colin Farquharson,José Luis Millán +6 more
TL;DR: It is shown that ablation of the OPN gene, Spp1, leads to improvements in the skeletal phenotype in Phospho1−/− as they age, and there is a clear dissociation in the hierarchical roles of these potent inhibitors of mineralization, with elevated PPi and elevated p‐OPN levels causing the respective skeletal phenotypes in Alpl/− and Ph phospho1/− mice.
Journal ArticleDOI
Bioactivity and osteoinductivity of glasses and glassceramics and their material determinants
TL;DR: The chemistry of bioglasses and glassceramics is highlighted that affects not only the formation of a stable implant/bone bonding by HAp layer, but also drives the cell response in vitro and in vivo.
Journal ArticleDOI
Phosphate induces formation of matrix vesicles during odontoblast-initiated mineralization in vitro.
Sandeep C. Chaudhary,Maria Kuzynski,Massimo Bottini,Elia Beniash,Terje Dokland,Callie G. Mobley,Manisha C. Yadav,Anne Poliard,Odile Kellermann,José Luis Millán,Dobrawa Napierala +10 more
TL;DR: It is determined that mineralization-competent MV are distinct from exosomes, and a new role of phosphate is identified in the process of ECM mineralization.
Journal ArticleDOI
Mesenchymal stem cell proliferation and mineralization but not osteogenic differentiation are strongly affected by extracellular pH.
Riham Fliefel,Riham Fliefel,Cvetan Popov,Matthias Tröltzsch,Jan Kühnisch,Michael Ehrenfeld,Sven Otto +6 more
TL;DR: P pH affected MSCs self-renewal and mineralization without influencing osteogenic differentiation, and future therapies, based on shifting acid-base balance toward the alkaline direction might be beneficial for prevention or treatment of osteomyelitis.
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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