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
More filters
Journal ArticleDOI
Hypophosphatasia: an overview of the disease and its treatment
TL;DR: This review presents the current knowledge on hypophosphatasia, a rare genetic disease of very variable severity (from lethal to mild) and clinical presentation, caused by defective production of tissue-non-specific alkaline phosphatase (TNSALP).
Journal ArticleDOI
Endothelial ZEB1 promotes angiogenesis-dependent bone formation and reverses osteoporosis
Rong Fu,Wen-Cong Lv,Ying Xu,Mu-Yun Gong,Xiao-Jie Chen,Nan Jiang,Yan Xu,Qingqiang Yao,Lei Di,Tao Lu,Liming Wang,Ran Mo,Zhao-Qiu Wu +12 more
TL;DR: It is shown that loss of ZEB1 in these cells epigenetically suppresses Notch signaling, leading to impaired angiogenesis and osteogenesis, and that Zeb1 delivery via liposomes ameliorates bone loss in osteoporotic mice.
Journal ArticleDOI
Burden of disease in adult patients with hypophosphatasia: Results from two patient-reported surveys.
TL;DR: The health profile of patients responding on the SF-12 showed a broad and substantial impact of HPP on health-related quality of life, with domains related to physical ability showing the greatest decrement compared to normative data.
Journal ArticleDOI
Staphylococcal Protein A, Panton-Valentine Leukocidin and Coagulase Aggravate the Bone Loss and Bone Destruction in Osteomyelitis
TL;DR: PVL, SpA and Coa play a critical role on bone loss and bone destruction of osteomyelitis.
Journal ArticleDOI
Vitamin D endocrinology of bone mineralization
TL;DR: The current knowledge of the role of the vitamin D endocrine system in controlling the mineralization process in bone is overview and vitamin D stimulation of human osteoblasts but is often found inhibitory for mineralization of murine osteoblast.
References
More filters
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.
Related Papers (5)
Enzyme-replacement therapy in life-threatening hypophosphatasia.
Michael P. Whyte,Cheryl R. Greenberg,Nada J. Salman,Michael B. Bober,William H. McAlister,Deborah Wenkert,Bradley J. Van Sickle,Jill H. Simmons,Terence S. Edgar,Martin L. Bauer,Mohamed A. Hamdan,Nick Bishop,Richard Lutz,Mairead McGinn,Stanley Craig,Jean N. Moore,John W. Taylor,Robert H. Cleveland,William R. Cranley,Ruth P. Lim,Tom D. Thacher,J. Mayhew,Matthew Downs,José Luis Millán,Alison Skrinar,Philippe Crine,Hal Landy +26 more