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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Methods of treating a subject with an alkaline phosphatase deficiency
TL;DR: In this paper, methods for treating a subject with an alkaline phosphatase deficiency, further comprising monitoring additional anaiytes, e.g., calcium, parathyroid hormone and/or vitamin D, are presented.
Journal ArticleDOI
Guiding bone formation using semi‐onlay calcium phosphate implants in an ovine calvarial model
Gry Hulsart Billström,Viviana R Lopes,Christopher Illies,Sara Gallinetti,Jonas Åberg,Håkan Engqvist,Conrado Aparicio,Sune Larsson,Lars Kihlström Burenstam Linder,Erik Birgersson +9 more
TL;DR: This study shows that CaP based implants can be assembled with the help of additive manufacturing to guide vertical bone formation without decortification or administration of growth factors.
Journal ArticleDOI
Revealing Prognostic Value of Skeletal-Related Parameters in Metastatic Castration-Resistant Prostate Cancer on Overall Survival: A Systematic Review and Meta-Analysis of Randomized Controlled Trial.
Tongyu Tong,Hanqi Lei,Yupeng Guan,Xiangwei Yang,Guolong Liao,Yamei Li,Donggen Jiang,Jun Pang +7 more
TL;DR: Higher levels of ALP/BSAP and uNTx, a higher BPI-SF score, and progression of BSI predict inferior OS in patients with mCRPC, and more randomized control trials are needed to investigate the promising value of these parameters.
Journal ArticleDOI
Ectopic Ocular Surface Calcification in Patients With Hypophosphatasia Treated With Asfotase Alfa
Sidney M. Gospe,Cecilia Santiago-Turla,Stephanie DeArmey,Thomas J. Cummings,Priya S. Kishnani,M. Tariq Bhatti +5 more
TL;DR: Asfotase alfa was invariably associated with development of mild focal conjunctival calcification, likely through disinhibition of hydroxyapatite crystal propagation, and should not preclude enzyme replacement therapy for patients with this rare and often debilitating disease.
Book ChapterDOI
Genetic Alterations: Heritable Dentin Defects
TL;DR: The genetic alterations of genes encoding proteins involved in dentin and bone formation reflecting the similarities between the two tissue development and homeostasis and subsequent clinical phenotypes are described.
References
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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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