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
Inhibition of alkaline phosphatase: an emerging new drug target.
Mariya al-Rashida,Jamshed Iqbal +1 more
TL;DR: This mini review has been written in the wake of mounting evidence of potential therapeutic benefits associated with inhibition of alkaline phosphatases and aims to provide prolific leads to design more potent and selective AP inhibitors.
Journal ArticleDOI
Hormonal regulation of biomineralization.
Andrew Arnold,Elaine M. Dennison,Christopher S. Kovacs,Michael Mannstadt,René Rizzoli,Maria-Luisa Brandi,Bart L. Clarke,Rajesh V. Thakker +7 more
TL;DR: How developmental stresses in the fetus and neonate, and in the mother during pregnancy and lactation, invoke alternative hormonal regulatory pathways to control mineral delivery, skeletal metabolism and biomineralization is summarized.
Journal ArticleDOI
How To Build a Bone: PHOSPHO1, Biomineralization, and Beyond
TL;DR: The evidence for PHOSPHO1's central role in the biomineralization of bone and other hard tissues is examined, along with emerging evidence of its activity in other systems including choline synthesis and homeostasis, and energy metabolism.
Journal ArticleDOI
Extracellular Phosphate Induces the Expression of Dentin Matrix Protein 1 Through the FGF Receptor in Osteoblasts.
Jin Nishino,Miwa Yamazaki,Masanobu Kawai,Kanako Tachikawa,Keiko Yamamoto,Kazuaki Miyagawa,Mikihiko Kogo,Keiichi Ozono,Toshimi Michigami +8 more
TL;DR: The results indicate that FGFR mediates the direct effects of extracellular Pi on the expression of Dmp1 in osteoblasts and enhance the close relationship between the signaling evoked by elevated extracllular Pi and FGF/FGFR signaling.
Journal ArticleDOI
Periodontal Defects in the A116T Knock-in Murine Model of Odontohypophosphatasia
Brian L. Foster,Campbell R. Sheen,Nan E. Hatch,J. Liu,Esther Cory,Sonoko Narisawa,Tina Kiffer-Moreira,Robert L. Sah,Michael P. Whyte,Martha J. Somerman,José Luis Millán +10 more
TL;DR: The Alpl+/A116T mouse is the first model of odontohypophosphatasia, providing insights on dentoalveolar development and function under reduced ALP, bringing attention to direct effects of HPP on alveolar bone, and offering a new model for testing potential dental-targeted therapies in future studies.
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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